Overview: Muscarinic acetylcholine receptors (nomenclature as agreed by NC-IUPHAR sub-committee on Muscarinic Acetylcholine Receptors, Caulfield and Birdsall, 1998) are 7TM receptors of the rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the table, AC-42 and desmethylclozapine have been described as selective agonists of the M1 receptor subtype via binding to a site distinct to that recognised by non-selective agonists (Spalding et al., 2002; Sur et al., 2003). There are two allosteric sites on muscarinic receptors, one defined by it binding gallamine, strychnine and brucine and the other binds KT5720, WIN62,577, WIN51,708 and staurosporine (Lazareno et al., 2000, 2002). There are selective enhancers of acetylcholine binding and action; brucine and KT5720 at M1 receptors, PG135 at M2 receptors, N-chloromethylbrucine and WIN62,577 at M3 receptors and thiochrome at M4 receptors (Birdsall and Lazareno, 2005). The allosteric site for gallamine and strychnine on M2 receptors can be labelled by [3H]dimethyl-W84 (Tränkle et al., 2003). THRX-160209 is a multivalent ligand that may achieve its selectivity for M2 receptors by binding both to the orthosteric and a nearby allosteric site (Steinfeld et al., 2007).
Antagonist data tabulated are pKi values determined for human recombinant receptors. MT3 (m4-toxin) and MT7 (m1-toxin1) are toxins contained with the venom of the Eastern green mamba (Dendroaspis augusticeps) (see Bradley, 2000; Potter et al., 2004).
Keywords:
Muscarinic acetylcholine receptors, acetylcholine, AC-42, desmethylclozapine, gallamine, strychnine, brucine, KT5720, WIN62,577, WIN51,708, staurosporine, M1 receptors, M2 receptors, M3 receptors, M4 receptors, M5 receptors, PG135, N-chloromethylbrucine, WIN62,577, thiochrome, [3H]dimethyl-W84, MT7, 4-DAMP, tripitramine, pirenzepine, guanylpirenzepine, darifenacin, AFDX384, MT3, himbacine, [3H]NMS, [3H]QNB, [3H]pirenzepine, [11C]xanomeline, [11C]butylthio-TZTP, [18F]FP-TZTP, [3H]darifenacin, MT3 (m4-toxin), MT7 (m1-toxin1)
Abbreviations:
4-DAMP, 4-diphenylacetoxy-N-methylpiperidine methiodide; AC-42, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride; AFDX116, (otenzepad), 1-[2-[2-(diethylaminomethyl)piperidin-1-yl]acetyl]-5H-pyrido[2,3-b][1,4]benozodiazepin-6-one; AFDX384, (
)-5,11-dihydro-11-([(2-[2-[dipropylamino)methyl]-1-piperidinyl)ethyl)amino)carbonyl)-6H-pyrido[2,3-b](1,4)benzodiazepine-6-one; Butylthio-TZTP, butylthio-thiadiazolyltetrahydro-1-methyl-pyridine; Dimethyl-W84, N,N'-bis[3-(1,3-dihydro-1,3-dioxo-4-methyl-2H-isoindol-2-yl)propyl]-N,N,N',N'-tetramethyl-1,6-hexanediaminium diiodide; FP-TZTP, [3-(3-(3-Fluoropropyl)thio)-1,2,5-thiadiazol-4-yl]1,2,5,6-tetrahydro-1-methylpyridine; KT5720, (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester; NMS, N-methylscopolamine; PG135, (3aS,12R,12aS,12bR)-2-amino-2,3,3a,4,11,12a,12b-octahydro-10-hydroxyisoquino[2,1,8-lma]carbazol-5(1H)-one hydrochloride; QNB, 3-quinuclidinylbenzilate; THRX160209, 4-{N-[7-(3-(S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl]-N-(n-propyl)amino}-1-(2,6-dimethoxy-benzyl)piperidine; WIN51,708, 17-
-hydroxy-17-
-ethynyl-5--androstano[3,2-b]pyrimido[1,2-a]benzimidazole; WIN62,577, 17--hydroxy-17--ethynyl-
4-androstano[3,2-b]pyrimido[1,2-a]benzimidazole
References
Further Reading
- Abrams P, Andersson KE, Buccafusco JI, Chapple C, De Groat WC, Fryer AD et al. (2006). Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 148: 565–578. | Article | PubMed | ISI | ChemPort |
- Birdsall NJM, Lazareno S (2005). Allosterism at muscarinic receptors: ligands and mechanisms. Mini Rev Med Chem 5: 523–543. | Article | PubMed | ISI | ChemPort |
- Bradley KN (2000). Muscarinic toxins from the green mamba. Pharmacol Ther 85: 87–109.
- Caulfield MP, Birdsall NJM (1998). International Union of Pharmacology. XVII Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50: 279–290. | PubMed | ISI | ChemPort |
- Eckelman WC (2006). Imaging of muscarinic receptors in the central nervous system. Curr Pharm Des 12: 3901–3913.
- Eglen RM (2005). Muscarinic receptor subtype pharmacology and physiology. Prog Med Chem 43: 105–136. | PubMed | ChemPort |
- Eglen RM (2006). Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autocoid Pharmacol 26: 219–233.
- Holzgrabe U, De Amici M, Mohr K (2006). Allosteric modulators and selective agonists of muscarinic receptors. J Mol Neurosci 30: 165–168.
- Ishii M, Kurachi Y (2006). Muscarinic acetylcholine receptors. Curr Pharm Des 12: 3573–3581.
- Potter LT, Flynn DD, Liang JS, McCollum MH (2004). Studies of muscarinic neurotransmission with antimuscarinic toxins. Prog Brain Res 145: 121–128.
- Wess J, Eglen RM, Gautam D (2007). Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov 6: 721–733. | Article | PubMed | ChemPort |
References
- Lazareno S et al. (2002). Mol Pharmacol 62: 1492–1505. | Article | PubMed | ISI | ChemPort |
- Lazareno S et al. (2000). Mol Pharmacol 58: 194–207. | PubMed | ISI | ChemPort |
- Spalding TA et al. (2002). Mol Pharmacol 61: 1297–1302. | Article | PubMed | ISI | ChemPort |
- Steinfeld T et al. (2007). Mol Pharmacol 72: 291–302. | Article |
- Sur C et al. (2003). Proc Natl Acad Sci USA 100: 13674–13679. | Article | PubMed | ChemPort |
- Tränkle C et al. (2003). Mol Pharmacol 64: 180–190. | PubMed |
