Muscarinic acetylcholine receptor M₅

Template:PBB The human muscarinic acetylcholine receptor M₅, encoded by the CHRM5 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 2009, 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]

Antagonists

VU-0488130 (ML381)^[6]
Xanomeline^[7]

References

^ Kou Qin, Chunmin Dong, Guangyu Wu & Nevin A Lambert (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Gentry PR, Kokubo M, Bridges TM, et al. (2014). "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)". J. Med. Chem. 57: 7804–10. doi:10.1021/jm500995y. PMID 25147929.
^ Gentry PR, Bridges TM, Lamsal A, et al. (2013). "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorg. Med. Chem. Lett. 23 (10): 2996–3000. doi:10.1016/j.bmcl.2013.03.032. PMID 23562060.
^ Bridges TM, Marlo JE, Niswender CM, et al. (June 2009). "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". J. Med. Chem. 52 (11): 3445–8. doi:10.1021/jm900286j. PMID 19438238.
^ Gentry PR, Kokubo M, Bridges TM, et al. (2013). "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)". J. Med. Chem. 56 (22): 9351–5. doi:10.1021/jm4013246. PMID 24164599.
^ Gentry PR, Kokubo M, Bridges TM, et al. (2014). "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. doi:10.1002/cmdc.201402051. PMID 24692176.
^ Grant MK, El-Fakahany EE (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M₅ receptor". J. Pharmacol. Exp. Ther. 315 (1): 313–9. doi:10.1124/jpet.105.090134. PMID 16002459.