CROSS-REFEENCE TO RELATED APPLICATIONS

[01] The present application claims priority under 35 U. S. C. §119 to U.S. Provisional application 63/282568, filed November 23, 2021, U.S. Provisional application 63/282616, filed November 23, 2021, and U.S. Provisional application 63/299320, filed January 13, 2022, the contents of which are hereby incorporated by reference in their entireties.

BACKRGROUND

[02] Acetylcholine (ACh), a neurotransmitter, can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, and cognitive functions. In the mammalian brain, nine different subunits have been identified, which assemble into pentameric complexes with much subunit diversity. The 0.7 and 0.402 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. The a7* and non-a7 nAChR subtypes are active targets for therapeutic development in neurodegenerative disease, neurodevelopmental disorders, and chronic pain. These receptors play a role in the etiology and treatment of such neurological disorders as Alzheimer’s disease (AD), autism, schizophrenia, neuropathic pain, and addiction.

[03] Smoking and substance abuse are preventable causes of serious diseases such as cancer, cardiovascular accidents, respiratory disorders, strokes and overdoses. Despite major prevention efforts to warn of the dangers of such consumption in some countries, notably through information campaigns, smoking, for example, has only moderately declined.

[04] There remains a need for alternative acetylcholine receptor agonists and associated therapeutic treatment methods for treating neurological disorders, including addiction to smoking tobacco or nicotine. SUMMARY

[05] According to one aspect, an acetylcholine receptor agonist has a structure selected from the group consisting of: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.

[06] According to another aspect, an acetylcholine receptor agonist has a structure selected from the group consisting of:

or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.

[07] According to a further aspect, an acetylcholine receptor agonist has a structure selected from the group consisting of: and or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.

[08] In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of at least one acetylcholine receptor agonist depicted above and a pharmaceutically acceptable vehicle therefor.

[09] In yet another aspect, a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist having the structure: and a pharmaceutically acceptable vehicle therefor.

[10] In yet another aspect, a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist having the structure: and a pharmaceutically acceptable vehicle therefor.

[11] In yet another aspect, a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist having the structure: and a pharmaceutically acceptable vehicle therefor. In some examples, the disorder is Alzheimer’s disease (AD), autism, schizophrenia, or neuropathic pain. In other examples, the disorder is depression, anxiety, or an addiction.

[12] In a particular aspect, the present disclosure provides a method for treatment or remedy of smoking addiction or promoting smoking cessation, comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist disclosed herein.

[13] In one aspect, the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of

, or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.

[14] In some embodiments, the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula la or Formula lb set forth below:

or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, and R5 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein RHs selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR ^A R ^B , — S-alkyl, — SO-alkyl, — SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R ^A and R ^B are each independently selected from hydrogen and Ci-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, — COOH, — C(O)— Ci-4 alkyl, — C(O)O— Ci-4 alkyl, NR ^C R ^D , —S-alkyl, —SO-alkyl and — SO ₂ -alkyl; wherein R ^c and R ^D are each independently selected from hydrogen and Ci-4 alkyl; and each - represents a single or double bond.

[15] In another aspect, the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula Ila or Formula lib set forth below:

or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, R5, and Re are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R4 is selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR ^A R ^B , — S-alkyl, — SO-alkyl, — SO2- alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R ^A and R ^B are each independently selected from hydrogen and Ci-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, — COOH, — C(O)— Ci-4 alkyl, — C(O)O— CM alkyl, NR ^C R ^D , —S-alkyl, —SO- alkyl and — SO2-alkyl; wherein R ^c and R ^D are each independently selected from hydrogen and Ci-4 alkyl; and each - represents a single or double bond.

[16] In some embodiments, wherein Ri has the structure according to Formula Illa or Formula Illb:

Formula Illa Formula Illb

, wherein X", A, B, Ri, R2, R3, R4 and each > - are defined as above.

[17] In some embodiments, A is N, B is C, and one of - is a double bond.

[18] In some embodiments, both A and B are N.

[19] In some embodiments, B is N, and R2 is nothing.

[20] In some embodiments, Ri, R2, and/or R3 is methyl.

[21] In some embodiments, R4 is a ketone.

[22] In some embodiments, one of > - is a double bond.

[23] In some embodiments, the acetylcholine receptor agonist has the structure:

, or a pharmaceutically acceptable ester or solvate thereof.

[24] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof. [25] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[26] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[27] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[28] In one aspect the present disclosure relates to an acetylcholine receptor agonist comprising

1-methyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l-ium, 2,2'-(pyridine-3,5-diyl)bis(l- methyl-2,5-dihydro-lH-pyrrol-l-ium), 2,2',2"-(pyridine-2,4,6-triyl)tris(l-methyl-2,5- dihydro-lH-pyrrol-l-ium), 3-(l -methyl -2, 5-dihydro-lH-imidazol-2-yl)pyri dine, 1-methyl-

2-(pyridin-3-yl)-2,5-dihydro-lH-imidazol-l-ium, 3-(3-methyl-3,4-dihydro-2H-pyrrol-2- yl)pyridine, 3-methyl-2-(pyridin-3-yl)-3,4-dihydro-2H-pyrrol-l-ium, l-methyl-2-phenyl- 2,5-dihydro-lH-imidazol-l-ium, l,4-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l- ium, 3-(l,4-dimethyl-2,5-dihydro-lH-pyrrol-2-yl)pyridine, l,4-dimethyl-2-(pyri din-3 -yl)- 2,5-dihydro-lH-imidazol-l-ium, 3-(l,4-dimethyl-2,5-dihydro-lH-imidazol-2-yl)pyridine, l,3-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-imidazol-3-ium, 3-(l,3-dimethyl-2,5- dihydro-lH-pyrrol-2-yl)pyridine, l,3-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l- ium, l,4-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l-ium, and l,4-dimethyl-2- (pyridin-2-yl)-2,5-dihydro-lH-pyrrol-l-ium, or a pharmaceutically acceptable ester or solvate thereof.

[29] In one aspect the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of:

, or a pharmaceutically acceptable ester or solvate thereof, wherein X" is defined as above.

[30] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein and a pharmaceutically acceptable vehicle therefor. [31] In another disclosure, the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof the pharmaceutical composition disclosed herein.

[32] In some embodiments, the disorder is depression.

[33] In some embodiments, the disorder is anxiety.

[34] In some embodiments, the disorder is neuropathic pain.

[35] In some embodiments, the disorder is Alzheimer’s disease.

[36] In some embodiments, the disorder is an addiction.

[37] In some embodiments, the addiction is tobacco or nicotine addiction.

[38] In some embodiments, the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:

, or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle therefor.

[39] In some embodiments, the disorder is depression.

[40] In some embodiments, the disorder is anxiety.

[41] In some embodiments, the disorder is neuropathic pain.

[42] In some embodiments, the disorder is Alzheimer’s disease. [43] In some embodiments, the disorder is an addiction.

[44] In some embodiments, the addiction is tobacco or nicotine addiction.

[45] In one aspect, the present disclosure relates to a method of treating nicotine addiction associated with smoking tobacco or promoting smoking cessation in a subject in need thereof, comprising administering a therapeutically effective amount of an acetylcholine receptor agonist or the pharmaceutical composition disclosed herein to the subject in need thereof. In some embodiments, the method of treating tobacco or nicotine addiction, or treating nicotine addiction associated with smoking tobacco or promoting smoking cessation comprises administering the acetylcholine receptor agonist having the structure: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt and a pharmaceutically acceptable vehicle therefor.

[46] In some embodiments, the methods disclosed herein result in at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction in an intensity of smoking tobacco or nicotine self-administration by a subject, or the subject no longer smokes tobacco or selfadministers tobacco.

[47] In some embodiments, the reduction in an intensity of smoking tobacco or nicotine selfadministration or cessation of smoking is observed after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[48] In some embodiments, treatment may continue for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or more days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 or weeks months; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more months; or 1, 2, or 3 or more years or until the subj ect no long experiences nicotine cravings or other nicotine withdrawal symptoms, or has ceased smoking or using other tobacco products. [49] In some embodiments, reduction in smoking intensity is determined by measuring expired carbon monoxide levels, or a biochemical marker of smoking intensity in biological fluids obtained from the subject.

[50] In some embodiments, the acetylcholine receptor agonist is administered at a dose of from about 0.01 to about 50 mg/kg.

[51] In some embodiments, the present disclosure relates to a composition for use in a method of treating a neurological disorder in a subject in need thereof, wherein the composition comprises an acetylcholine receptor agonist disclosed herein or is the pharmaceutical compositions disclosed herein, and wherein the method comprises administering the composition to the subject.

[52] In some embodiments, the present disclosure relates to an acetylcholine receptor agonist disclosed herein for use in the manufacture of a medicament for treating a neurological disorder.

DETAILED DESCRIPTION

[53] Nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of cys-loop receptors, which also includes serotonin 5-HT3, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (GABA)A, GAB AC, and glycine receptors, and participate in a variety of physiological functions, including regulation of neuronal excitability and neurotransmitter release. The nAChRs are widely distributed throughout the peripheral nervous system (PMS) and the CNS, as well as the immune system and various peripheral tissues. In the mammalian brain, nine different nAChR subunits are known to exist (a2-7 and [32— 4), which combine as either homo- or heteromeric complexes into multiple functionally diverse pentameric receptors. The predominant subtypes functionally expressed in the brain are categorized as a7* subunit-containing receptors (either homo- or heteromeric) or those composed of both a and P subunits, including the a4p2* and a3p4* subtypes (the * denotes that these nAChRs can contain other a and P subunits as well).

[54] The a4p2* receptor subtype was initially found to be the maj or nAChR subtype in the brain (where it comprises 90% of the high affinity nicotine binding sites, while the a3p4* nAChR is known primarily as a ganglionic receptor in the PNS. The a3p4* nAChR is also expressed in a variety of brain areas, including the interpeduncular nucleus and medial habenula. In addition, the a2, a5, a6, and 03 subunits participate in nAChRs expressed in various brain regions, although they represent a minority population of the total.

[55] The al* nAChR subunit is a key therapeutic target as these receptors are expressed on a variety of cell types in the periphery, including immune cells and neurons, as well as in the brain regions that underlie learning and memory. Further, these receptors are highly permeable to calcium, implicating them as significant modulators of intracellular signaling and neurotransmitter release from neurons. In the brain, al* receptors are expressed on both neurons and non-neuronal cells, including astrocytes, microglia, oligodendrocyte precursor cells, endothelial cells, and chondroitin sulfate proteoglycan NG2-expressing (NG2) cells, among others. Expression of al* receptors in these non-neuronal cells suggests a possible role in brain innate immunity, inflammation, and neuroprotection. Immune cell expression of al* receptors has been shown to modulate inflammatory responses by regulating the production of inflammatory cytokines and chemokines.

[56] While the al* nAChR was initially thought to be functionally expressed as homomeric receptors, it recently has been shown to be capable of co-assembling with other subunits, which provides an explanation for the incongruent properties of in situ a7-containing receptors and in vitro expressed homomeric al receptors. Dineley et al., Trends in Pharm. Sci., Feb. 2015, Vol. 36, No. 2, reported that al and 02 subunits co-assembled in vitro, and that basal forebrain cholinergic neurons express functional a702 receptors with an enhanced sensitivity to the amyloid-0 (A0) peptide associated with AD.

[57] Acetylcholine receptor agonists of the present invention

[58] In one aspect, the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of:

or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt. In another aspect, the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of

or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt. [59] In some embodiments, the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula la or Formula lb set forth below:

Formula la or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, and R5 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein RHs selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR ^A R ^B , — S-alkyl, — SO-alkyl, — SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R ^A and R ^B are each independently selected from hydrogen and Ci-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, — COOH, — C(O)— Ci-4 alkyl, — C(O)O— Ci-4 alkyl, NR ^C R ^D , —S-alkyl, —SO-alkyl and — SO ₂ -alkyl; wherein R ^c and R ^D are each independently selected from hydrogen and Ci-4 alkyl; and each - represents a single or double bond. [60] In another aspect, the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula Ila or Formula lib set forth below: or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, R5, and Re are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R4 is selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR ^A R ^B , — S-alkyl, — SO-alkyl, — SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R ^A and R ^B are each independently selected from hydrogen and Ci-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, — O-alkyl, — COOH, — C(O)— Ci-4 alkyl, — C(O)O— Ci-4 alkyl, NR ^C R ^D , — S-alkyl, — SO-alkyl and — SO2-alkyl; wherein R ^c and R ^D are each independently selected from hydrogen and Ci-4 alkyl; and each - represents a single or double bond.

[61] In some embodiments, Ri has the structure according to Formula Ila or Formula lib :

Formula Illa Formula Illb

, wherein X", A, B, Ri, R2, R3, R4 and each > - are defined as above.

[62] In some embodiments, A is N, B is C, and one of - is a double bond. .

[63] In some embodiments, both A and B are N.

[64] In some embodiments, B is N, and R2 is nothing.

[65] In some embodiments, RI, R2, and/or R3 is methyl.

[66] In some embodiments, R4 is a ketone.

[67] In some embodiments, one of > - is a double bond.

[68] In some embodiments, the acetylcholine receptor agonist has the structure:

, or a pharmaceutically acceptable ester or solvate thereof.

[69] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof. [70] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[71] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[72] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[73] In some embodiments, X" may be an ion formed from l-hydroxy-2-naphthoic acid, 2,2- di chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2- disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene- 1,5 -di sulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), or undecylenic acid.

[74] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.

[75] In another aspect, an acetylcholine receptor agonist has a structure selected from the group consisting of:

or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt. For example, X" may be an ion formed from 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthal ene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), or undecylenic acid.

[76] In one aspect the present disclosure relates to an acetylcholine receptor agonist comprising

1-methyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l-ium, 2,2'-(pyridine-3,5-diyl)bis(l- methyl-2,5-dihydro-lH-pyrrol-l-ium), 2,2',2"-(pyridine-2,4,6-triyl)tris(l-methyl-2,5- dihydro-lH-pyrrol-l-ium), 3-(l -methyl -2, 5-dihydro-lH-imidazol-2-yl)pyri dine, 1-methyl-

2-(pyridin-3-yl)-2,5-dihydro-lH-imidazol-l-ium, 3-(3-methyl-3,4-dihydro-2H-pyrrol-2- yl)pyridine, 3-methyl-2-(pyridin-3-yl)-3,4-dihydro-2H-pyrrol-l-ium, l-methyl-2-phenyl- 2,5-dihydro-lH-imidazol-l-ium, l,4-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l- ium, 3-(l,4-dimethyl-2,5-dihydro-lH-pyrrol-2-yl)pyridine, l,4-dimethyl-2-(pyri din-3 -yl)- 2,5-dihydro-lH-imidazol-l-ium, 3-(l,4-dimethyl-2,5-dihydro-lH-imidazol-2-yl)pyridine, 1 , 3 -dimethyl-2-(pyri din-3 -yl)-2, 5 -dihydro- 1 H-imidazol-3 -ium, 3 -( 1 , 3 -dimethy 1-2, 5 - dihydro-lH-pyrrol-2-yl)pyridine, l,3-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l- ium, l,4-dimethyl-2-(pyridin-3-yl)-2,5-dihydro-lH-pyrrol-l-ium, and l,4-dimethyl-2- (pyridin-2-yl)-2,5-dihydro-lH-pyrrol-l-ium, or a pharmaceutically acceptable ester or solvate thereof.

[77] In another aspect, an acetylcholine receptor agonist has a structure selected from the group consisting of: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt. For example, X" may be an ion formed from 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthal ene-l,5-disulfonic acid, naphthal ene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), or undecylenic acid.

[78] In one aspect the present disclosure relates to an acetylcholine receptor agonist having the structure selected from the group consisting of:

, or a pharmaceutically acceptable ester or solvate thereof, wherein X" is defined as above. [79] In some embodiments, the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.

[80] Pharmaceutical compositions containing the acetylcholine receptor agonists disclosed herein and uses thereof

[81] A pharmaceutical composition may include a pharmaceutically acceptable carrier that facilitates processing of an active ingredient into pharmaceutically acceptable compositions. As used herein, the term “pharmacologically acceptable carrier” is synonymous with “pharmacological carrier” and means any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary” or “excipient.” Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharmaceutically acceptable carriers can be used including, without limitation, aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like; solid carriers such as, e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient. Selection of a pharmacologically acceptable carrier can depend on the mode of administration. Except insofar as any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated. Nonlimiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman’s The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). These protocols are routine procedures and any modifications are well within the scope of one skilled in the art and from the teaching herein.

[82] Compounds intended for administration to humans or other mammals generally should have very high purity. Purity refers to the ratio of a compound’s mass to the total sample mass following any purification steps. Usually, the level of purity is at least about 95%, more usually at least about 96%, about 97%, about 98%, or higher. For example, the level of purity may be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.

[83] Compound described herein that exist in more than one optical isomer form (enantiomer) may be provided either as a racemic mixture or by isolating one of the enantiomers, the latter case in which purity as described above may refer to enantiomeric purity. [84] The compounds described herein may be prepared synthetically using such techniques as those described in K. Huang et al., “A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues,” J Heterocycl Chem. 2009 Nov 6; 46(6): 1252-1258, doi: 10.1002/jhet.233; or Riah et al., “Synthesis of Cotinine and Cotinine N-oxide: Evaluation of their Interaction with Nicotine in the Insecticidal Activity,” J. Nat. Prod. Letters, Vol. 11 (1997), https://doi.org/10.1080/10575639708043755, with appropriate modifications to reagents to obtain the disclosed structures as will be apparent to persons skilled in the art with the aid of no more than routine experimentation.

[85] In some aspects, a compound may be converted into a pharmaceutically acceptable salts using techniques well known to persons skilled in the art. For example, salts such as sodium and potassium salts may be prepared by treating the compound with a suitable sodium or potassium base, such as sodium hydroxide or potassium hydroxide, respectively. Esters and ethers of the compound may be prepared as described, e.g., in Advanced Organic Chemistry, 1992, 4th Edition, J. March, John Wiley & Sons, or J. Med. Chemistry, 1992, 35, 145-151.

[86] A pharmaceutical composition may optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like. Various buffers and means for adjusting pH can be used to prepare a pharmaceutical composition disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers. It is understood that acids or bases can be used to adjust the pH of a composition as needed. Pharmaceutically acceptable antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTP A, and CaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor. The pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition.

[87] Examples of auxiliaries and/or excipients that may be mentioned are cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, carboxymethylcellulose sodium, talc, agar-agar, mineral oil, animal oil, vegtetable oil, organic and mineral waxes, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycols, tween 80, solutol HS 15, and water. It is also possible to administer the active substances as such, without vehicles or diluents, in a suitable form, for example, in capsules.

[88] Compositions described herein may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other modes of administration known to persons skilled in the art. In some examples, compositions may be formulated for delivery by inhaler, e-cigarette/vape, gum, transdermal patch, or similar techniques. In some aspects, the compositions may be used as a nicotine substitute for individuals afflicted with tobacco addiction, inclusive of smoking addiction and smokeless tobacco addiction.

[89] A pharmaceutical composition may comprise a therapeutic compound in an amount sufficient to allow customary administration to an individual. A unit dose form may have, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound. In other aspects, a unit dose form may have, e.g., at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a therapeutic compound. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may include, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg of a therapeutic compound. In still other aspects of this embodiment, a pharmaceutical composition disclosed herein may include, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg of a therapeutic compound.

[90] In some aspects, the acetylcholine receptor agonists disclosed herein have antiinflammatory activity. For example, a compound may have an anti-inflammatory activity capable of reducing the levels of an inflammation-inducing molecule, such as substance P(SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof. A compound may have an anti-inflammatory activity capable of reducing the levels of SP, CGRP, glutamate, or a combination thereof released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.

[91] Prostaglandins mediate a local inflammatory response and are involved in all inflammatory functions through action on prostaglandin receptors and mediate inflammatory signaling including chemotaxis (macrophages, neutrophils and eosinophils), vasodilation and algesia. However, the PG-mediated inflammatory response is self-limiting (resolving). The principle resolution factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxisome proliferator-activator receptor-y (PPAR-y) signaling. PPAR-y signaling pathway 1) induces apoptosis of macrophage Ml cells, thereby reducing the levels of Thl pro-inflammatory cytokines and 2) promotes differentiation of monocytes into macrophage M2 cells. Macrophage M2 cells produce and release Th2 anti-inflammatory cytokines. [92] Compounds disclosed herein may have an anti-inflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin. A compound may have an antiinflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. A compound may have an anti-inflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin released from a sensory neuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[93] The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. All PPARs are known to heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes called peroxisome proliferator hormone response elements (PPREs). PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. The family comprises three members, PPAR-a, PPAR-y, and PPAR-6 (also known as PPAR-P). PPAR-a is expressed in liver, kidney, heart, muscle, adipose tissue, as well as other tissues. PPAR-6 is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPAR-y comprises three alternatively-spliced forms, each with a different expression pattern. PPAR-yl is expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen. PPAR-y2 is expressed mainly in adipose tissue. PPAR- y3 is expressed in macrophages, large intestine, and white adipose tissue. Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPAR-y is activated by PGD2 (a prostaglandin), whereas PPAR-a is activated by leukotriene B4. [94] A compound may have an anti-inflammatory activity capable of reducing the levels of IFN- y, TNF-a, IL-12, or a combination thereof released from a Thl cell and increasing the levels of IL-10 released from a Th2 cell. A compound may have an anti-inflammatory activity capable of reducing the levels of IFN-y, TNF-a, IL-12, or a combination thereof released from a Thl cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%, and capable of increasing the levels of IL-10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.

[95] A compound may have an anti-inflammatory activity capable of stimulating some or all PPAR signaling pathways. It is contemplated that such a compound therefore may act as a PPAR pan-agonist or possibly as a selective PPAR agonist.

[96] A compound may have an anti-inflammatory activity capable of modulating Thl and Th2 cytokines. A compound may have an anti-inflammatory activity capable of reducing the levels of Interferon-y (IFN-y), tumor necrosis factor-a (TNF-a), interleukin- 12 (IL-12), or a combination thereof released from a Thl cell. A compound may have an anti-inflammatory activity capable of reducing the levels of IFN-y, TNF-a, IL-12, or a combination thereof released from a Thl cell by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. A compound may have an anti-inflammatory activity capable of reducing the levels of IFN-y, TNF-a, IL-12, or a combination thereof released from a Thl cell in a range from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 10% to about 90.

[97] A compound may have an anti-inflammatory activity capable of increasing the levels of IL- 10 released from a Th2 cell. A compound may have an anti-inflammatory activity capable of increasing the levels of IL- 10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.

[98] In one aspect, the compounds herein may be useful for treating acute or chronic inflammation.

[99] A chronic inflammation symptom can be associated with a large, otherwise unrelated group of disorders which underlay a variety of diseases and disorders. The immune system is often involved with chronic inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with etiological origins in chronic inflammatory processes include cancer, atherosclerosis, and ischaemic heart disease. Non-limiting examples of disorders exhibiting chronic inflammation as a symptom include, without limitation, acne, acid reflux/heartburn, age related macular degeneration (AMD), allergy, allergic rhinitis, Alzheimer’s disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, Crohn’s disease, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington’s disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), a migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson’s disease, parotitis, pelvic inflammatory disease, pemphigus vularis, pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sarcopenia, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complication, synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis.

[100] In some embodiments, the acetylcholine receptor agonist is administered at a dose of from about 0.01 to about 50 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 20 mg/kg, about 0.1 mg/kg to about 18 mg/kg, about 1 mg/kg to about 16 mg/kg, about 2 mg/kg to about 14 mg/kg, or about 5 mg/kg to about 10 mg/kg. In some embodiments, the acetylcholine receptor agonist is administered at a dose of about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8/5 mg/kg, about 9 mg/kg, about 9.5 mg/kg, about 10 mg/kg, about 10.5 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 13.5 mg/kg, about 14 mg/kg, about 14.5 mg/kg, about 15 mg/kg, about 15.5 mg/kg, about 16 mg/kg, about 16.5 mg/kg, about 17 mg/kg, about 17.5 mg/kg, about 18 mg/kg, about 18.5 mg/kg, about 19 mg/kg, about 19.5 mg/kg, about 20 mg/kg about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg. In some embodiments, the acetylcholine receptor agonist is administered at a dose of about 0.5 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, or about 2500 mg.

[101] Pharmaceutical compositions as described herein may include a pharmaceutically acceptable solvent. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous (the solute), resulting in a solution. Solvents useful in the pharmaceutical compositions include, without limitation, a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent and a pharmaceutically acceptable non-polar solvent. A pharmaceutically acceptable polar aprotic solvent includes, without limitation, di chloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO). A pharmaceutically acceptable polar protic solvent includes, without limitation, acetic acid, formic acid, ethanol, n-butanol, 1 -butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water. A pharmaceutically acceptable non-polar solvent includes, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-di oxane, chloroform, n-methyl- pyrrolidone (NMP), and diethyl ether.

[102] The method of administration as well as the dosage range which are suitable in a specific case depend on the species to be treated and on the state of the respective condition or disease, and may be optimized using techniques known in the art. Most often, the daily dose of active compound in a patient may range from 0.0005 mg to 15 mg per kg, more usually 0.001 mg to 7.5 mg per kg. Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For instance, treatment may comprise a one-time administration of an effective dose of a pharmaceutical composition as disclosed herein. Alternatively, treatment may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual’s symptoms. For example, an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.

[103] Pharmaceutical compositions may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with acceptable pharmaceutical or food grade acids, bases or buffers to enhance the stability of the formulated composition or its delivery form.

[104] Liquid dosage forms for oral administration include acceptable pharmaceutical or food grade emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylsulfoxide (DMSO) dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[105] Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, acceptable pharmaceutical or food grade excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agaragar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and j) sweetening, flavoring, perfuming agents, and mixtures thereof. In the case of capsules, lozenges, tablets and pills, the dosage form may also comprise buffering agents. [106] The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract or, optionally, in a delayed or extended manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Tablet formulations for extended release are also described in U.S. Pat. No. 5,942,244.

[107] Compositions may contain a compound as disclosed herein, alone or with other therapeutic compound(s). A therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals. A therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g., a hydrochloride. Additionally, therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers, including an R- or S-enantiomer. Thus, the therapeutic compound disclosed herein may comprise an R-enantiomer only, a S-enantiomer only, or a combination of both an R- enantiomer and a S-enantiomer of a therapeutic compound. In some aspects, the therapeutic compound may have anti-inflammatory activity, such as a non-steroidal anti-inflammatory drug (NSAID). NSAIDs are a large group of therapeutic compounds with analgesic, antiinflammatory, and anti-pyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase. NSAIDs include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac. [108] NSAIDs may be classified based on their chemical structure or mechanism of action. Nonlimiting examples of NSAIDs include a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase- 1 (COX-1) inhibitor, and a selective cyclooxygenase-2 (COX-2) inhibitor. An NSAID may be a profen. Examples of a suitable salicylate derivative NSAID include, without limitation, acetylsalicylic acid (aspirin), diflunisal, and salsalate. Examples of a suitable p-amino phenol derivative NSAID include, without limitation, paracetamol and phenacetin. Examples of a suitable propionic acid derivative NSAID include, without limitation, alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Examples of a suitable acetic acid derivative NSAID include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac. Examples of a suitable enolic acid (oxicam) derivative NSAID include, without limitation, droxicam, isoxicam, lomoxicam, meloxicam, piroxicam, and tenoxicam. Examples of a suitable fenamic acid derivative NSAID include, without limitation, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of a suitable selective COX-2 inhibitors include, without limitation, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[109] In some embodiments, the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle therefor.

[110] In another aspect, a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a compound having the structure: or a pharmaceutically acceptable ester or solvate thereof.

[Hl] In some embodiments, the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure according to Formula la or Formula lb:

Formula la

[112] or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, and R5 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein RHs selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR ^A R ^B , — S-alkyl, — SO-alkyl, — SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R ^A and R ^B are each independently selected from hydrogen and Ci-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, — COOH, — C(O)— Ci-4 alkyl, — C(O)O— Ci-4 alkyl, NR ^C R ^D , —S-alkyl, —SO-alkyl and — SO ₂ -alkyl; wherein R ^c and R ^D are each independently selected from hydrogen and Ci-4 alkyl; and each - represents a single or double bond.

[113] In another aspect, the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula Ila or Formula lib set forth below: or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, R5, and Re are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R4 is selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR ^A R ^B , — S-alkyl, — SO-alkyl, — SO2- alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R ^A and R ^B are each independently selected from hydrogen and Ci-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, — COOH, — C(O)— Ci-4 alkyl, — C(O)O— CM alkyl, NR ^C R ^D , — S-alkyl, — SO- alkyl and — SO2-alkyl; wherein R ^c and R ^D are each independently selected from hydrogen and Ci-4 alkyl; and each - represents a single or double bond.

[114] In some embodiments, the disorder is depression. Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and/or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and/or abnormal hormonal circadian rhythms.

[115] In some embodiments, the disorder is anxiety.

[116] In some embodiments, the disorder is neuropathic pain.

[117] In some embodiments, the disorder is Alzheimer’s disease.

[118] In some embodiments, the disorder is an addiction. In some embodiments, the addiction includes addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.

[119] The compounds disclosed herein may be particularly suitable for treating neurological disorders such as Alzheimer’s Disease (AD), autism, schizophrenia, addiction, anxiety, depression, and neuropathic pain. Addiction is inclusive of addictions to controlled substances (opioid, heroin, cocaine, barbiturate, methamphetamine, etc.) addiction as well as addiction to tobacco, inclusive of smoking and smokeless tobacco addiction. [120] Use of acetylcholine receptor agonist for promoting smoking cessation or treating tobacco or nicotine addiction

[121] In some embodiments, the present disclosure relates to a method of treating nicotine addiction associated with smoking tobacco comprising administering a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein. Some embodiments include a method of treating nicotine addiction associated with smoking tobacco comprising administering an acetylcholine receptor agonist disclosed herein. In some embodiments, the method of treating tobacco or nicotine addiction, or promoting smoking cessation comprises administering a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein. In a preferred embodiment, the method of treating tobacco or nicotine addiction, or treating nicotine addiction associated with smoking tobacco or promoting smoking cessation comprises administering the acetylcholine receptor agonist having the structure: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt and a pharmaceutically acceptable vehicle therefor.

[122] In some embodiments, the therapeutically effective amount of a acetylcholine receptor agonist disclosed herein is administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days. In some embodiments, the methods comprise administering an acetylcholine receptor agonist (or composition comprising the same) three or more times a day, twice a day, or once a day.

[123] In some embodiments, the method of treating tobacco or nicotine addiction, or promoting smoking cessation comprises administering a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein results in at least 10% reduction in an intensity of smoking tobacco or nicotine self-administration by a subject. In some embodiments, the reduction in an intensity of smoking tobacco or nicotine selfadministration by a subject is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100%, or the subject no longer smokes tobacco or self-administer nicotine. The reduction in an intensity of smoking tobacco or nicotine self-administration or cessation of smoking is observed after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks; or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months; or after 1 year, 2 years, 3 years, etc. In some embodiments, the methods comprise administering a single dose of an acetylcholine receptor agonist (or composition comprising the same). In some embodiments, the method comprises administering repeated doses, such as for a predetermined period of time of until the symptoms or effects of nicotine addiction are reduced, ameliorated, or eliminated or until the subject has ceased smoking or otherwise consuming In such embodiments, the nicotine-degrading enzyme variant may be a long-acting nicotine-degrading enzyme variant as described above. In some embodiments, treatment is repeated with additional doses if signs/symptoms/effects persist or if the subject continues to have nicotine cravings or experiences them anew. In some embodiments, treatment may continue for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or more days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 or weeks months; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more months; or 1, 2, or 3 or more years or until the subject no long experiences nicotine cravings or other nicotine withdrawal symptoms, or has ceased smoking or using other tobacco products. In some embodiments, administration of the compounds disclosed herein to human beings results in the reduction of smoking intensity as measured using the number of cigarettes smoked per day, assessed via daily smoking diaries. In some embodiments, the reduction in smoking intensity is determined by measuring expired carbon monoxide levels, or a biochemical marker of smoking intensity (such as nicotine or cotinine) in biological fluids obtained from the subject.

[124] In some embodiments, the therapeutically effective dosage of the acetylcholine receptor agonist disclosed herein may depend on the weight or age of the subject, the intensity of smoking, and/or the level of nicotine in the subject's brain or plasma at the time of treatment. In some embodiments, the acetylcholine receptor agonist is administered at a dose of from about 0.01 to about 50 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 20 mg/kg, about 0.1 mg/kg to about 18 mg/kg, about 1 mg/kg to about 16 mg/kg, about 2 mg/kg to about 14 mg/kg, or about 5 mg/kg to about 10 mg/kg. In some embodiments, the acetylcholine receptor agonist is administered at a dose of about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8/5 mg/kg, about 9 mg/kg, about 9.5 mg/kg, about 10 mg/kg, about 10.5 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 13.5 mg/kg, about 14 mg/kg, about 14.5 mg/kg, about 15 mg/kg, about 15.5 mg/kg, about 16 mg/kg, about 16.5 mg/kg, about 17 mg/kg, about 17.5 mg/kg, about 18 mg/kg, about 18.5 mg/kg, about 19 mg/kg, about 19.5 mg/kg, about 20 mg/kg about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg. In some embodiments, the acetylcholine receptor agonist is administered at a dose of about 0.5 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, or about 2500 mg.

[125] In some embodiments, a subject in need of treatment for nicotine addiction or promoting smoking cessation is a human subject who consumes nicotine products, such as smoking tobacco, chewing tobacco, electronic cigarettes, and/or other nicotine delivery devices. Such a subject may or may not be physically addicted to nicotine and/or psychologically addicted to consuming nicotine products. Typical subjects in need of smoking cessation treatment smoke or use tobacco or other nicotine products daily, such as smoking at least 1 cigarette a day, or more, such as at least about 5, at least about 10, at least about 15, at least about 20, or more, cigarettes per day, including fewer than 10, 10-20, 20-30, 30-40, or 40 or more (or the equivalent use of other tobacco or nicotine products). [126] Definitions

[127] As used herein, the singular forms “a”, “an” and “the” are used interchangeably and intended to include the plural forms as well and fall within each meaning, unless the context clearly indicates otherwise. Also, as used herein, “and/or” refers to and encompasses any and all possible permutations and combinations of one or more of the listed items.

[128] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[129] As used herein, the phrases “therapeutically effective amount” and “therapeutic level” mean an acetylcholine receptor agonist disclosed herein dosage or plasma concentration in a subject that provides the specific pharmacological effect for which the acetylcholine receptor agonist disclosed herein is administered to a subject in need of such treatment, i.e. to promote smoking cessation and/or treat tobacco or nicotine addiction. The therapeutically effective amount may vary based on the route of administration and dosage form, the age and weight of the subject, and/or the subject's condition. In the context of promoting smoking cessation or treating tobacco or nicotine addiction, the subject’s condition may for example include the degree of nicotine addiction, amount of nicotine generally consumed/ingested by the subject, and/or the subject's plasma levels of nicotine at the time of treatment and/or the amount of nicotine localized in the brain at the time of treatment.

[130] The terms “treatment” or “treating” as used herein refer to one or more of: reducing, ameliorating or eliminating one or more symptoms or effects of the disease or condition. In the context of smoking cessation or treating nicotine addiction, such symptoms may include nicotine withdrawal; reducing the number of cigarettes or the amount of nicotine consumed by a subject; and/or reducing the subject's plasma levels of nicotine and/or reducing the amount of nicotine localized in specific tissues of the subject (e.g., brain/central nervous system, heart and vasculature, etc.), and/or reducing the subject’s levels of expired carbon monoxide, and/or reducing the subject’s levels of a biochemical marker of tobacco smoking or nicotine self-admini strati on in a biological fluid. [131] The terms “individual,” “subject,” and “patient” are used interchangeably herein, and refer to any individual mammal subject, e.g., bovine, canine, feline, equine, or human. In accordance with FDA guidance, as used herein, “child” refers to a human subject from 0 through about 19 years of age. A child can be a subject that begins a course of treatment prior to turning about 19 years of age, even if the subject continues treatment beyond 19 years of age.

[132] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[133] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[134] While the invention has been described with respect to specific examples, those skilled in the art will appreciate that there are numerous variations and permutations of the above described systems and techniques that fall within the spirit and scope of the invention as set forth in the appended claims.