Muscarinic acetylcholine receptor

Amanita muscaria, the mushroom from which muscarine was isolated.

Acetylcholine - the natural agonist of muscarinic and nicotinic receptors.

Muscarine - an agonist used to distinguish between these two classes of receptors. Not normally found in the body.

Atropine - an antagonist.

Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certain neurons^[1] and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.

Muscarinic receptors were named as such because they are more sensitive to muscarine than to nicotine.^[2] Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.^[3]

Function

Acetylcholine (ACh) is a neurotransmitter found in the brain, neuromuscular junctions and the autonomic ganglia. Muscarinic receptors are used in the following roles:

Recovery receptors

The structure of Muscarinic acetylcholine receptor M2

ACh is always used as the transmitter within the autonomic ganglion. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization (Fast EPSP) of that neuron. As a consequence of this, nicotinic receptors are often cited as the receptor on the postganglionic neurons at the ganglion. However, the subsequent hyperpolarization (IPSP) and slow depolarization (Slow EPSP) that represent the recovery of the postganglionic neuron from stimulation are actually mediated by muscarinic receptors, types M₂ and M₁ respectively (discussed below) .

Peripheral autonomic fibers (sympathetic and parasympathetic fibers) are categorized anatomically as either preganglionic or postganglionic fibers, then further generalized as either adrenergic fibers, with their corresponding adrenergic receptors, or cholinergic fibers, with their cholinergic receptors. Both preganglionic sympathetic fibers and preganglionic parasympathetic fibers are cholinergic. All postganglionic sympathetic fibers are adrenergic; their neurotransmitter is norepinephrine, except for the postganglionic sympathetic fibers to the sweat glands, piloerectile muscles of the body hairs, and the skeletal muscle arterioles.

The adrenal medulla is considered a sympathetic ganglion and, like other sympathetic ganglia, is supplied by cholinergic preganglionic sympathetic fibers; acetylcholine is its neurotransmitter. The other postganglionic fibers of the peripheral autonomic system belong to the parasympathetic division; all are cholinergic fibers, and use acetylcholine (ACh) as their neurotransmitter.

Postganglionic neurons

Another role for these receptors is at the junction of the innervated tissues and the postganglionic neurons in the parasympathetic division of the autonomic nervous system. Here acetylcholine is again used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue.

Innervated tissue

Very few parts of the sympathetic system use cholinergic receptors. In sweat glands the receptors are of the muscarinic type. The sympathetic nervous system also has some preganglionic nerves terminating at the chromaffin cells in the adrenal medulla, which secrete epinephrine and norepinephrine into the bloodstream. Some believe that chromaffin cells are modified postganglionic CNS fibers. In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type.

The somatic nervous system uses a nicotinic receptor to acetylcholine at the neuromuscular junction.

Higher central nervous system

Muscarinic acetylcholine receptors are also present and distributed throughout the central nervous system, in post-synaptic and pre-synaptic positions. There is also some evidence for postsynaptic receptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects.

Presynaptic membrane of the neuromuscular junction

It's now known they also appear on the pre-synaptic membrane of somatic neurons in the neuro-muscular junction, where they are involved in the regulation of acetylcholine release.

Form of muscarinic receptors

Muscarinic acetylcholine receptors belong to a class of metabotropic receptors that use G proteins as their signalling mechanism. In such receptors, the signaling molecule (the ligand) binds to a receptor that has seven transmembrane regions; in this case, the ligand is ACh. This receptor is bound to intracellular proteins, known as G proteins, which begin the information cascade within the cell.^[4]

By contrast, nicotinic receptors use a ligand-gated ion channel mechanism for signaling. In this case, binding of the ligands with the receptor causes an ion channel to open, permitting either one or more specific type(s) of ion (e.g., K⁺, Na⁺, Ca²⁺) to diffuse into or out of the cell.

Receptor isoforms

Classification

By the use of selective radioactively labeled agonist and antagonist substances, five subtypes of muscarinic receptors have been determined, named M₁-M₅ (using an upper case M and subscript number).^[5] M₁,M₃,M₅ receptors are coupled with Gq proteins, while M₂ and M₄ receptors are coupled with G_i/o proteins.^[4] There are other classification systems. For example, the drug pirenzepine is a muscarinic antagonist (decreases the effect of ACh), which is much more potent at M₁ receptors than it is at other subtypes. The acceptance of the various subtypes has proceeded in numerical order: therefore, sources that recognize only the M₁/M₂ distinction exist. More recent studies tend to recognize M₃ and the most recent M₄.

Genetic differences

Meanwhile, geneticists and molecular biologists have characterised five genes that appear to encode muscarinic receptors, named m1-m5 (lowercase m; no subscript number). The first four code for pharmacologic types M₁-M₄. The fifth, M₅, corresponds to a subtype of receptor that had until recently not been detected pharmacologically. The receptors m1 and m2 were determined based upon partial sequencing of M₁ and M₂ receptor proteins. The others were found by searching for homology, using bioinformatic techniques.

Difference in G proteins

Comparison of types
Type	Gene	Function	PTX	CTX	Effectors	Agonists^[8]	Antagonists^[8]
M₁	CHRM1	EPSP in autonomic ganglia secretion from salivary glands and stomach In CNS activates slow after-depolarizing potentials in neurons ^[9]^[10]^[11]	no (yes)	no (yes)	G_q (G_i) (G_s): Slow EPSP. ↓ K⁺ conductance^[11]^[12]	acetylcholine oxotremorine muscarine carbachol^[11] McNA343^[11] 77-LH-28-1	atropine^[11] Hyoscyamine^[13] scopolamine^[11] Diphenhydramine Dimenhydrinate dicycloverine^[11] Thorazine tolterodine^[11] oxybutynin^[11] ipratropium^[11] mamba toxin MT7^[11] mamba toxin MT1^[14] mamba toxin MT2^[15] pirenzepine telenzepine chlorpromazine haloperidol
M₂	CHRM2	slow heart rate reduce contractile forces of atrium reduce conduction velocity of AV node In CNS homotropic inhibition	yes	no	G_i ↑ K⁺ conductance^[11] ↓ Ca²⁺ conductance^[11]	acetylcholine methacholine carbachol^[11] oxotremorine^[11] muscarine	atropine^[11] hyoscyamine^[13] dicycloverine^[11] Thorazine Diphenhydramine Dimenhydrinate tolterodine^[11] oxybutynin^[11] ipratropium^[11] methoctramine^[16] tripitramine gallamine chlorpromazine
M₃	CHRM3	smooth muscle contraction bronchoconstriction Increase intracellular calcium in vascular endothelium increased endocrine and exocrine gland secretions, e.g. salivary glands and stomach In CNS Eye accommodation vasodilation induce emesis	no	no	G_q	acetylcholine^[4] bethanechol carbachol^[4]^[11] oxotremorine^[11] pilocarpine (in eye)	atropine^[4]^[11] hyoscyamine^[13] Diphenhydramine Dimenhydrinate dicycloverine^[11] tolterodine^[11] oxybutynin^[11] ipratropium^[11] darifenacin tiotropium
M₄	CHRM4	Activation of M4 causes decreased locomotion^[11] In CNS	yes	?	G_i ↑ K⁺ conductance^[11] ↓ Ca²⁺ conductance^[11]	acetylcholine carbachol^[11] oxotremorine^[11]	atropine^[11] Diphenhydramine Dimenhydrinate dicycloverine^[11] tolterodine^[11] oxybutynin^[11] ipratropium^[11] mamba toxin MT1^[14] mamba toxin MT2^[15] mamba toxin MT3^[11]
M₅	CHRM5	In CNS	no	?	G_q	acetylcholine carbachol^[11] oxotremorine^[11]	atropine^[11] Diphenhydramine Dimenhydrinate dicycloverine^[11] tolterodine^[11] oxybutynin^[11] ipratropium^[11]

M₁ receptor

Main article: Muscarinic acetylcholine receptor M1

This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS.^[17]^[18]

It is predominantly found bound to G proteins of class G_q,^[19] which use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, G_i (causing a downstream decrease in cAMP) and G_s (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX, respectively.

M₂ receptor

Main article: Muscarinic acetylcholine receptor M2

The M₂ muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after stimulatory actions of the sympathetic nervous system, by slowing the speed of depolarization. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). It also serves to slightly decrease the contractile forces of the ventricular muscle.

M₂ muscarinic receptors act via a G_i type receptor, which causes a decrease in cAMP in the cell, inhibition of voltage-gated Ca²⁺ channels, and increasing efflux of K⁺, in general, leading to inhibitory-type effects.

M₃ receptor

Main article: Muscarinic acetylcholine receptor M3

The M₃ muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. Because the M₃ receptor is G_q-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during bronchoconstriction and bladder voiding.^[20] However, with respect to vasculature, activation of M₃ on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M₃ mediates vasconstriction in pathologies wherein the vascular endothelium is disrupted.^[21] The M₃ receptors are also located in many glands, which help to stimulate secretion in, for example, the salivary glands, as well as other glands of the body.

Like the M₁ muscarinic receptor, M₃ receptors are G proteins of class G_q that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.^[4]

M₄ receptor

Main article: Muscarinic acetylcholine receptor M4

M₄ receptors are found in the CNS.

Receptors work via G_i receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. Possible bronchospasm may result if stimulated by muscarinic agonists

M₅ receptor

Main article: Muscarinic acetylcholine receptor M5

Location of M₅ receptors is not well known.

Like the M₁ and M₃ muscarinic receptor, M₅ receptors are coupled with G proteins of class G_q that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.

Pharmacological application

Ligands targeting the mAChR that are currently approved for clinical use include non-selective antagonists for the treatment of Parkinson's disease,^[22] atropine (to dilate the pupil), Scopolamine (used to prevent motion sickness), and ipratropium (used in the treatment of COPD).^[3]

References

↑ Eglen RM (July 2006). "Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function". Auton Autacoid Pharmacol 26 (3): 219–33. doi:10.1111/j.1474-8673.2006.00368.x. PMID 16879488.
↑ Ishii M, Kurachi Y (2006). "Muscarinic acetylcholine receptors". Curr. Pharm. Des. 12 (28): 3573–81. doi:10.2174/138161206778522056. PMID 17073660.
1 2 Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 122–6. ISBN 978-0-87893-697-7.
1 2 3 4 5 6 Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology 7 (11): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
↑ Caulfield MP, Birdsall NJ (1 June 1998). "International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors". Pharmacol. Rev. 50 (2): 279–90. PMID 9647869.
↑ Simon MI, Strathmann MP, Gautam N (1991). "Diversity of G proteins in signal transduction". Science 252 (5007): 802–8. doi:10.1126/science.1902986. PMID 1902986.
↑ Dell'Acqua ML, Carroll RC, Peralta EG (15 March 1993). "Transfected m2 muscarinic acetylcholine receptors couple to G alpha i2 and G alpha i3 in Chinese hamster ovary cells. Activation and desensitization of the phospholipase C signaling pathway". J. Biol. Chem. 268 (8): 5676–85. PMID 8449930.
1 2 Tripathi KD (2004). Essentials of Medical Pharmacology (5th ed.). India: Jaypee Brothers, Medical Publishers. pp. 890 pages. ISBN 81-8061-187-6. if nothing else mentioned in table
↑ Smith, Richard; Araneda, Ricardo (2010). "Cholinergic modulation of neuronal excitability in the accessory olfactory bulb". Journal of Neurophysiology 106: 2963–2974. doi:10.1152/jn.00446.2010. PMID 20861438. Retrieved 15 July 2015.
↑ Egorov, Alexei (2002). "Graded persistent activity in entorhinal cortex neurons". Nature 420: 173–178. doi:10.1038/nature01171. PMID 12432392. Retrieved 15 July 2015.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. p. 139. ISBN 0-443-07145-4.
↑ Uchimura N, North RA (1990). "Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones". J. Physiol. (Lond.) 422 (1): 369–80. doi:10.1113/jphysiol.1990.sp017989. PMC 1190137. PMID 1693682.
1 2 3 Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved January 13, 2013.
1 2 Servent D, Blanchet G, Mourier G, Marquer C, Marcon E, Fruchart-Gaillard C (August 2011). "Muscarinic toxins". Toxicon 58 (6-7): 455–463. doi:10.1016/j.toxicon.2011.08.004. PMID 21906611.
1 2 Karlsson E, Jolkkonen M, Mulugeta E, Onali P, Adem A (September 2000). "Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors.". Biochimie 82 (9-10): 793–806. doi:10.1016/S0300-9084(00)01176-7. PMID 11086210.
↑ Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J (December 1987). "Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine". European Journal of Pharmacology 144 (2): 117–124. doi:10.1016/0014-2999(87)90509-7. PMID 3436364.
↑ Johnson, Gordon (2002). PDQ Pharmacology (2nd ed.). Hamilton, Ontario: BC Decker Inc. pp. 311 pages. ISBN 1-55009-109-3.
↑ Richelson, Elliott (2000). "Cholinergic Transduction, Psychopharmacology - The Fourth Generation of Progress". American College of Neuropsychopharmacology. Retrieved 2007-10-27.
↑ Burford NT, Nahorski SR (1996). "Muscarinic M₁ receptor-stimulated adenylate cyclase activity in Chinese hamster ovary cells is mediated by Gs alpha and is not a consequence of phosphoinositidase C activation". Biochem. J. 315 (3): 883–8. PMC 1217289. PMID 8645172.
↑ Moro C, Uchiyama J, Chess-Williams R (December 2011). "Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol". Urology. 76 (6): 1442.e9–15. doi:10.1016/j.urology.2011.08.039. PMID 22001099.
↑ Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred (2006). Goodman & Gilman's the pharmacological basis of therapeutics (11th ed.). New York: McGraw-Hill. p. 185. ISBN 0-07-142280-3.
↑ Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacol. Ther. 117 (2): 232–43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893.

External links

"Acetylcholine Receptors (Muscarinic)". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Receptors, Muscarinic at the US National Library of Medicine Medical Subject Headings (MeSH)

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)

Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)

Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Adhesion	ADGRG (1 2 3 4 5 6 7)

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	Calcium-sensing receptor GABA B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F: Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

Cholinergics

Receptor ligands

mACh	Agonists: 77-LH-28-1 AC-42 AC-260,584 Aceclidine Acetylcholine AF30 AF150(S) AF267B AFDX-384 Alvameline AQRA-741 Arecoline Bethanechol Butyrylcholine Carbachol CDD-0034 CDD-0078 CDD-0097 CDD-0098 CDD-0102 Cevimeline Choline cis-Dioxolane Ethoxysebacylcholine Itameline LY-593,039 L-689,660 LY-2,033,298 McNA343 Methacholine Milameline Muscarine NGX-267 Ocvimeline Oxotremorine PD-151,832 Pilocarpine RS86 Sabcomeline SDZ 210-086 Sebacylcholine Suberyldicholine Talsaclidine Tazomeline Thiopilocarpine Vedaclidine VU-0029767 VU-0090157 VU-0152099 VU-0152100 VU-0238429 WAY-132,983 Xanomeline YM-796 Antagonists: 3-Quinuclidinyl benzilate 4-DAMP Aclidinium bromide Anisodamine Anisodine Antihistamines (first-generation) (e.g., brompheniramine, chlorphenamine, cyproheptadine, dimenhydrinate, diphenhydramine, doxylamine, mepyramine (pyrilamine), phenindamine, pheniramine, promethazine, tripelennamine, triprolidine) Atropine Atropine methonitrate Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, zotepine) Benactyzine Benzatropine (benztropine) Benzilylcholine mustard Benzydamine BIBN 99 Biperiden Bornaprine CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Dimethindene Dexetimide DIBD Dicyclomine (dicycloverine) Ditran EA-3167 EA-3443 EA-3580 EA-3834 Etanautine Etybenzatropine (ethybenztropine) Flavoxate Himbacine HL-031,120 Ipratropium bromide J-104,129 Hyoscyamine Mamba toxin 3 Mamba toxin 7 Mazaticol Mebeverine Methoctramine Metixene N-Ethyl-3-piperidyl benzilate N-Methyl-3-piperidyl benzilate Orphenadrine Otenzepad Oxybutynin PBID PD-102,807 PD-0298029 Phenglutarimide Phenyltoloxamine Pirenzepine Piroheptine Procyclidine Profenamine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine (hyoscine) Solifenacin Telenzepine Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin, mirtazapine) Tiotropium bromide Tolterodine Tricyclic antidepressants (e.g., amitriptyline, butriptyline, clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine) Trihexyphenidyl Tripitamine Tropatepine Tropicamide Typical antipsychotics (e.g., chlorpromazine, loxapine, thioridazine) WIN-2299 Xanomeline Zamifenacin

nACh	Agonists: 5-HIAA A-84,543 A-366,833 A-582,941 A-867,744 ABT-202 ABT-418 ABT-560 ABT-894 Acetylcholine Altinicline Anabasine Anatoxin-a AR-R17779 Butinoline Butyrylcholine Carbachol Choline Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethanol Ethoxysebacylcholine EVP-4473 EVP-6124 Galantamine GTS-21 Ispronicline Ivermectin Levamisole Lobeline MEM-63,908 (RG-3487) Morantel Nicotine (tobacco) NS-1738 PHA-543,613 PHA-709,829 PNU-120,596 PNU-282,987 Pozanicline Rivanicline RJR-2429 Sazetidine A SB-206553 Sebacylcholine SIB-1508Y SIB-1553A SSR-180,711 Suberyldicholine Suxamethonium (succinylcholine) TC-1698 TC-1734 TC-1827 TC-2216 TC-5214 TC-5619 TC-6683 Tebanicline Tropisetron UB-165 Varenicline WAY-317,538 XY-4083 Antagonists: 18-MAC 18-MC α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others) ABT-126 Alcuronium Allopregnanolone Amantadine Anatruxonium AQW051 Atracurium Barbiturates (e.g., pentobarbital, sodium thiopental) Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin) Bupropion Chandonium Chlorisondamine Cisatracurium Coclaurine Coronaridine Cyclopropane Dacuronium Decamethonium Dehydronorketamine Desflurane Dextromethorphan Dextropropoxyphene Dextrorphan Diadonium DHβE Dihydrochandonium Dimethyltubocurarine (metocurine) Dipyrandium Dizocilpine (MK-801) Doxacurium Encenicline Enflurane Esketamine Fazadinium Gallamine Halothane Hexafluronium Hexamethonium (benzohexonium) Hydroxybupropion Hydroxynorketamine Ibogaine Isoflurane Ketamine Kynurenic acid Laudexium (laudolissin) Levacetylmethadol Levomethadone Malouetine ME-18-MC Mecamylamine Memantine Methadone Methorphan (racemethorphan) Methyllycaconitine Metocurine Mivacurium Morphanol (racemorphan) Neramexane Nitrous oxide Norketamine Pancuronium bromide Pempidine Pentamine Pentolinium Phencyclidine Pipecuronium Progesterone Promegestone Radafaxine Rapacuronium Reboxetine Rocuronium Sevoflurane Surugatoxin Thiocolchicoside Toxiferine Tramadol Trimetaphan camsilate (trimethaphan camsylate) Tropeinium Tubocurarine Vanoxerine Vecuronium Xenon

Transporter ligands

CHT	Inhibitors: Hemicholinium-3 (hemicholine) Triethylcholine Enhancers: Coluracetam

VAChT	Inhibitors: Vesamicol

Enzyme modulators

ChAT	Inhibitors: 1-(-Benzoylethyl)pyridinium 2-(α-Naphthoyl)ethyltrimethylammonium 3-Chloro-4-stillbazole 4-(1-Naphthylvinyl)pyridine Acetylseco hemicholinium-3 Acryloylcholine AF64A B115 BETA CM-54,903 N,N-Dimethylaminoethylacrylate N,N-Dimethylaminoethylchloroacetate

AChE	Inhibitors: Reversible: Carbamates: Aldicarb Bendiocarb Bufencarb Caffeine Carbaryl Carbendazim Carbetamide Carbofuran Chlorbufam Chloropropham Ethienocarb Ethiofencarb Fenobucarb Fenoxycarb Formetanate Furadan Ladostigil Methiocarb Methomyl Miotine Oxamyl Phenmedipham Pinmicarb Pirimicarb Propamocarb Propham Propoxur; Stigmines: Distigmine bromide Eptastigmine Ganstigmine Neostigmine Phenserine Physostigmine Pyridostigmine bromide Quilostigmine Rivastigmine Terestigmine; Others: Acotiamide Ambenonium Donepezil Caffeine Edrophonium Galantamine Huperzine A Ipidacrine Minaprine Tacrine Zanapezil Irreversible: Organophosphates: Acephate Azinphos-methyl Bensulide Cadusafos Chlorethoxyfos Chlorfenvinphos Chlorpyrifos Chlorpyrifos-methyl Coumaphos Cyclosarin Demeton Demeton-S-methyl Diazinon Dichlorvos Dicrotophos Diisopropyl fluorophosphate Diisopropylphosphate Dimethoate Dioxathion Disulfoton EA-3148 Echothiophate Ethion Ethoprop Fenamiphos Fenitrothion Fenthion Fosthiazate GV Isofluorophate Isoxathion Malaoxon Malathion Methamidophos Methidathion Metrifonate Mevinphos Monocrotophos Naled Novichok agent Omethoate Oxydemeton-methyl Paraoxon Parathion Parathion-methyl Phorate Phosalone Phosmet Phoxim Pirimiphos-methyl Sarin Soman Tabun Tebupirimfos Temefos Terbufos Tetrachlorvinphos Tribufos Trichlorfon VE VG VM VR VX; Others: Demecarium Fasciculins (green mamba toxins) (1, 2, 3, 4) Onchidal (Onchidella binneyi) Reactivators: Asoxime Obidoxime Pralidoxime

BChE	Inhibitors: Cymserine Many of the AChE inhibitors listed above

Release modulators

Inhibitors	SNAP-25 inactivators: Botulinum toxin (A, C, E) VAMP inactivators: Botulinum toxin (B, D, F, G) Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)

Enhancers	LPHN agonists: α-Latrotoxin Others: Atracotoxin (e.g., robustoxin, versutoxin) Crotoxin

Others

Precursors	Choline (lecithin) Citicoline Cyprodenate Dimethylethanolamine Glycerophosphocholine Meclofenoxate (centrophenoxine) Phosphatidylcholine Phosphatidylethanolamine Phosphorylcholine Pirisudanol

Cofactors	Acetic acid Acetylcarnitine Acetyl-coA Vitamin B₅

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