Muscarinic acetylcholine receptor M5

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 Gq protein.[5] 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).

CHRM5
Identifiers
AliasesCHRM5, HM5, cholinergic receptor muscarinic 5
External IDsOMIM: 118496 MGI: 109248 HomoloGene: 22697 GeneCards: CHRM5
Orthologs
SpeciesHumanMouse
Entrez

1133

213788

Ensembl

ENSG00000184984

ENSMUSG00000074939

UniProt

P08912

Q920H4

RefSeq (mRNA)

NM_012125
NM_001320917

NM_205783

RefSeq (protein)

NP_001307846
NP_036257

NP_991352

Location (UCSC)Chr 15: 33.97 – 34.07 MbChr 2: 112.31 – 112.31 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

Negative allosteric modulators

Antagonists

See also

References

  1. GRCh38: Ensembl release 89: ENSG00000184984 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000074939 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology. 7 (10): 740–7. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
  6. Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, et al. (September 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)". Journal of Medicinal Chemistry. 57 (18): 7804–10. doi:10.1021/jm500995y. PMC 4175000. PMID 25147929.
  7. Gentry PR, Bridges TM, Lamsal A, Vinson PN, Smith E, Chase P, et al. (May 2013). "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorganic & Medicinal Chemistry Letters. 23 (10): 2996–3000. doi:10.1016/j.bmcl.2013.03.032. PMC 3634896. PMID 23562060.
  8. Bridges TM, Marlo JE, Niswender CM, Jones CK, Jadhav SB, Gentry PR, 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". Journal of Medicinal Chemistry. 52 (11): 3445–8. doi:10.1021/jm900286j. PMC 3875304. PMID 19438238.
  9. Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, et al. (November 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)". Journal of Medicinal Chemistry. 56 (22): 9351–5. doi:10.1021/jm4013246. PMC 3876027. PMID 24164599.
  10. McGowan KM, Nance KD, Cho HP, Bridges TM, Conn PJ, Jones CK, Lindsley CW (March 2017). "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. doi:10.1016/j.bmcl.2017.02.020. PMC 5508536. PMID 28237763.
  11. Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, et al. (August 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. PMC 4116439. PMID 24692176.
  12. Grant MK, El-Fakahany EE (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". The Journal of Pharmacology and Experimental Therapeutics. 315 (1): 313–9. doi:10.1124/jpet.105.090134. PMID 16002459. S2CID 11016091.

Further reading

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