Muscarinic acetylcholine receptor M5 explained

The human muscarinic acetylcholine receptor M₅, encoded by the gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to G_q protein.^[1] Binding of the endogenous ligand acetylcholine to the M₅ receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).

Ligands

No highly selective agonists or antagonists for the M₅ receptor have been discovered as of 2018, but several non-selective muscarinic agonists and antagonists have significant affinity for M₅.

The lack of selective M5 receptor ligands is one of the main reasons that the medical community has such a limited understanding of the M5 receptors effects as the possibility that any and/or all effects of non-selective ligands may be due to interactions with other receptors can not be ruled out. Some data may be obtained by observing which effects are common among semi-selective ligands (ex. a ligand of M1 and M5, a ligand of M2 and M5, and a ligand of M3 and M5), but until both a selective agonist and a selective antagonist of the M5 receptor are developed this data must be considered merely theoretical.

Agonists

• Milameline ((E)-1,2,5,6-Tetrahydro-1-methyl-3-pyridinecarboxaldehyde-O-methyloxime, CAS# 139886-32-1)
• Sabcomeline

Positive allosteric modulators

• ML-380^[2]
• ML-326^[3]
• VU-0238429: EC₅₀ = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.^[4]

Negative allosteric modulators

• ML375^[5]
• VU6008667^[6]

Antagonists

• VU-0488130 (ML381)^[7]
• Xanomeline^[8]
• Diphenhydramine
• Doxylamine

See also

• Muscarinic acetylcholine receptor

Further reading

• Book: Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV . Chapter 12: Muscarinic acetylcholine receptor subtypes: Localization and structure/Function . Cholinergic Function and Dysfunction . Progress in Brain Research . 1993 . 98 . 121–7 . 8248499 . 10.1016/S0079-6123(08)62388-2 . 9780444897176 .
• Gutkind JS, Novotny EA, Brann MR, Robbins KC . Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes . Proceedings of the National Academy of Sciences of the United States of America . 88 . 11 . 4703–7 . June 1991 . 1905013 . 51734 . 10.1073/pnas.88.11.4703 . 1991PNAS...88.4703G . free .
• Liao CF, Themmen AP, Joho R, Barberis C, Birnbaumer M, Birnbaumer L . Molecular cloning and expression of a fifth muscarinic acetylcholine receptor . The Journal of Biological Chemistry . 264 . 13 . 7328–37 . May 1989 . 10.1016/S0021-9258(18)83237-9 . 2540186 . free .
• Bonner TI, Young AC, Brann MR, Buckley NJ . Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes . Neuron . 1 . 5 . 403–10 . July 1988 . 3272174 . 10.1016/0896-6273(88)90190-0 . 833230 .
• Crespo P, Xu N, Daniotti JL, Troppmair J, Rapp UR, Gutkind JS . Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. Evidence for a protein kinase C-independent pathway . The Journal of Biological Chemistry . 269 . 33 . 21103–9 . August 1994 . 10.1016/S0021-9258(17)31935-X . 8063729 . free .
• Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H . Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C . The Journal of Biological Chemistry . 271 . 5 . 2776–82 . February 1996 . 8576254 . 10.1074/jbc.271.5.2776 . free .
• Kohn EC, Alessandro R, Probst J, Jacobs W, Brilley E, Felder CC . Identification and molecular characterization of a m5 muscarinic receptor in A2058 human melanoma cells. Coupling to inhibition of adenylyl cyclase and stimulation of phospholipase A2 . The Journal of Biological Chemistry . 271 . 29 . 17476–84 . July 1996 . 8663391 . 10.1074/jbc.271.29.17476 . free.
• Burstein ES, Spalding TA, Brann MR . The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling . The Journal of Biological Chemistry . 273 . 38 . 24322–7 . September 1998 . 9733718 . 10.1074/jbc.273.38.24322 . free.
• Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K . Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines . Neuroscience Letters . 266 . 1 . 17–20 . April 1999 . 10336173 . 10.1016/S0304-3940(99)00259-1 . 43548155 .
• Wang H, Han H, Zhang L, Shi H, Schram G, Nattel S, Wang Z . Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart . Molecular Pharmacology . 59 . 5 . 1029–36 . May 2001 . 11306684 . 10.1124/mol.59.5.1029 .
• Buchli R, Ndoye A, Arredondo J, Webber RJ, Grando SA . Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes . Molecular and Cellular Biochemistry . 228 . 1–2 . 57–72 . December 2001 . 11855742 . 10.1023/A:1013368509855 . 10788646 .
• Fujii T, Watanabe Y, Inoue T, Kawashima K . Upregulation of mRNA encoding the M5 muscarinic acetylcholine receptor in human T- and B-lymphocytes during immunological responses . Neurochemical Research . 28 . 3–4 . 423–9 . April 2003 . 12675126 . 10.1023/A:1022840416292 . 38866084 .
• De Luca V, Wang H, Squassina A, Wong GW, Yeomans J, Kennedy JL . Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia . Neuropsychobiology . 50 . 2 . 124–7 . 2004 . 15292665 . 10.1159/000079102 . 29032926 .
• Qu J, Zhou X, Xie R, Zhang L, Hu D, Li H, Lu F . The presence of m1 to m5 receptors in human sclera: evidence of the sclera as a potential site of action for muscarinic receptor antagonists . Current Eye Research . 31 . 7–8 . 587–97 . 2006 . 16877267 . 10.1080/02713680600770609 . 3218557 .
• Anney RJ, Lotfi-Miri M, Olsson CA, Reid SC, Hemphill SA, Patton GC . Variation in the gene coding for the M5 muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction: evidence from a prospective population based cohort study of young adults . BMC Genetics . 8 . 46 . July 2007 . 17608938 . 1978498 . 10.1186/1471-2156-8-46 . free .

Notes and References

1. Qin K, Dong C, Wu G, Lambert NA . Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers . Nature Chemical Biology . 7 . 10 . 740–7 . August 2011 . 21873996 . 3177959 . 10.1038/nchembio.642 .
2. Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Wood MR . 6 . Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380) . Journal of Medicinal Chemistry . 57 . 18 . 7804–10 . September 2014 . 25147929 . 4175000 . 10.1021/jm500995y .
3. Gentry PR, Bridges TM, Lamsal A, Vinson PN, Smith E, Chase P, Hodder PS, Engers JL, Niswender CM, Daniels JS, Conn PJ, Wood MR, Lindsley CW . 6 . Discovery of ML326: The first sub-micromolar, selective M5 PAM . Bioorganic & Medicinal Chemistry Letters . 23 . 10 . 2996–3000 . May 2013 . 23562060 . 3634896 . 10.1016/j.bmcl.2013.03.032 .
4. Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, Plumley HC, Weaver CD, Conn PJ, Lindsley CW . 6 . Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins . Journal of Medicinal Chemistry . 52 . 11 . 3445–8 . June 2009 . 19438238 . 3875304 . 10.1021/jm900286j .
5. Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Wood MR, Lindsley CW . 6 . Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375) . Journal of Medicinal Chemistry . 56 . 22 . 9351–5 . November 2013 . 24164599 . 3876027 . 10.1021/jm4013246 .
6. McGowan KM, Nance KD, Cho HP, Bridges TM, Conn PJ, Jones CK, Lindsley CW . 5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies . Bioorganic & Medicinal Chemistry Letters . 27 . 6 . 1356–1359 . March 2017 . 28237763 . 5508536 . 10.1016/j.bmcl.2017.02.020 .
7. Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, Hodder PS, Utley TJ, Rajapakse A, Byers F, Niswender CM, Morrison RD, Daniels JS, Wood MR, Conn PJ, Lindsley CW . 6 . Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe . ChemMedChem . 9 . 8 . 1677–82 . August 2014 . 24692176 . 4116439 . 10.1002/cmdc.201402051 .
8. Grant MK, El-Fakahany EE . Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor . The Journal of Pharmacology and Experimental Therapeutics . 315 . 1 . 313–9 . October 2005 . 16002459 . 10.1124/jpet.105.090134 . 11016091 .