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Muscarinic acetylcholine receptor M5

Protein-coding gene in the species Homo sapiens

Summary

Protein-coding gene in the species Homo sapiens

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 Gq protein. 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

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

Positive allosteric modulators

  • ML-380
  • ML-326
  • VU-0238429: EC50 = 1.16 μM; 30-fold selectivity versus M1 and M3, inactive at M2 and M4.

Negative allosteric modulators

  • ML375
  • VU6008667

Antagonists

  • VU-0488130 (ML381)
  • VU6036864
  • Xanomeline
  • Diphenhydramine
  • Doxylamine

References

References

  1. (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology.
  2. (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.
  3. (May 2013). "Discovery of ML326: The first sub-micromolar, selective M5 PAM". Bioorganic & Medicinal Chemistry Letters.
  4. (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.
  5. (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.
  6. (March 2017). "5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies". Bioorganic & Medicinal Chemistry Letters.
  7. (August 2014). "Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe". ChemMedChem.
  8. (October 2005). "Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor". The Journal of Pharmacology and Experimental Therapeutics.
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g-protein-coupled-receptors human-proteins muscarinic-acetylcholine-receptors
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