Muscarinic acetylcholine receptor M5: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
|||
| Line 5: | Line 5: | ||
==Ligands== | ==Ligands== | ||
No highly selective agonists or antagonists for the M<sub>5</sub> receptor have been discovered as of | No highly selective agonists or antagonists for the M<sub>5</sub> receptor have been discovered as of 2018, but several non-selective muscarinic agonists and antagonists have significant affinity for M<sub>5</sub>. | ||
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. | 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. | ||
| Line 16: | Line 16: | ||
* ML-380<ref name="pmid25147929">{{cite journal |vauthors=Gentry PR, Kokubo M, Bridges TM, etal |title=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=J. Med. Chem. |volume= 57|issue= |pages= 7804–10|year=2014 |pmid=25147929 |doi=10.1021/jm500995y |pmc=4175000}}</ref> | * ML-380<ref name="pmid25147929">{{cite journal |vauthors=Gentry PR, Kokubo M, Bridges TM, etal |title=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=J. Med. Chem. |volume= 57|issue= |pages= 7804–10|year=2014 |pmid=25147929 |doi=10.1021/jm500995y |pmc=4175000}}</ref> | ||
* ML-326<ref name="pmid23562060">{{cite journal |vauthors=Gentry PR, Bridges TM, Lamsal A, etal |title=Discovery of ML326: The first sub-micromolar, selective M5 PAM |journal=Bioorg. Med. Chem. Lett. |volume=23 |issue=10 |pages=2996–3000 |year=2013 |pmid=23562060 |doi=10.1016/j.bmcl.2013.03.032 |pmc=3634896}}</ref> | * ML-326<ref name="pmid23562060">{{cite journal |vauthors=Gentry PR, Bridges TM, Lamsal A, etal |title=Discovery of ML326: The first sub-micromolar, selective M5 PAM |journal=Bioorg. Med. Chem. Lett. |volume=23 |issue=10 |pages=2996–3000 |year=2013 |pmid=23562060 |doi=10.1016/j.bmcl.2013.03.032 |pmc=3634896}}</ref> | ||
* [[VU-0238429]]: [[Half maximal effective concentration|EC<sub>50</sub>]] = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.<ref name="pmid19438238">{{cite journal |vauthors=Bridges TM, Marlo JE, Niswender CM, etal |title=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=J. Med. Chem. |volume=52 |issue=11 |pages=3445–8 |date=June 2009 |pmid=19438238 |doi=10.1021/jm900286j |url=}}</ref> | * [[VU-0238429]]: [[Half maximal effective concentration|EC<sub>50</sub>]] = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.<ref name="pmid19438238">{{cite journal |vauthors=Bridges TM, Marlo JE, Niswender CM, etal |title=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=J. Med. Chem. |volume=52 |issue=11 |pages=3445–8 |date=June 2009 |pmid=19438238 |doi=10.1021/jm900286j |url=|pmc=3875304 }}</ref> | ||
===Negative allosteric modulators=== | ===Negative allosteric modulators=== | ||
| Line 70: | Line 70: | ||
{{DEFAULTSORT:Muscarinic Acetylcholine Receptor M5}} | {{DEFAULTSORT:Muscarinic Acetylcholine Receptor M5}} | ||
[[Category:G protein coupled receptors]] | [[Category:G protein-coupled receptors]] | ||
[[Category:Human proteins]] | [[Category:Human proteins]] | ||
[[Category:Muscarinic acetylcholine receptors]] | [[Category:Muscarinic acetylcholine receptors]] | ||
Revision as of 23:52, 6 November 2018
| VALUE_ERROR (nil) | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Aliases | |||||||
| External IDs | GeneCards: [1] | ||||||
| Orthologs | |||||||
| Species | Human | Mouse | |||||
| Entrez |
|
| |||||
| Ensembl |
|
| |||||
| UniProt |
|
| |||||
| RefSeq (mRNA) |
|
| |||||
| RefSeq (protein) |
|
| |||||
| Location (UCSC) | n/a | n/a | |||||
| PubMed search | n/a | n/a | |||||
| Wikidata | |||||||
| |||||||
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.[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
Antagonists
- VU-0488130 (ML381)[6]
- Xanomeline[7]
See also
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.
- ↑ 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. PMC 4175000. 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. PMC 3634896. 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. PMC 3875304. 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. PMC 3876027. 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. PMC 4116439. 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.
Further reading
- Brann MR, Ellis J, Jørgensen H, et al. (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function". Prog. Brain Res. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499.
- Gutkind JS, Novotny EA, Brann MR, Robbins KC (1991). "Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes". Proc. Natl. Acad. Sci. U.S.A. 88 (11): 4703–7. doi:10.1073/pnas.88.11.4703. PMC 51734. PMID 1905013.
- Liao CF, Themmen AP, Joho R, et al. (1989). "Molecular cloning and expression of a fifth muscarinic acetylcholine receptor". J. Biol. Chem. 264 (13): 7328–37. PMID 2540186.
- Bonner TI, Young AC, Brann MR, Buckley NJ (1990). "Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes". Neuron. 1 (5): 403–10. doi:10.1016/0896-6273(88)90190-0. PMID 3272174.
- Crespo P, Xu N, Daniotti JL, et al. (1994). "Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. Evidence for a protein kinase C-independent pathway". J. Biol. Chem. 269 (33): 21103–9. PMID 8063729.
- Haga K, Kameyama K, Haga T, et al. (1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.". J. Biol. Chem. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID 8576254.
- Kohn EC, Alessandro R, Probst J, et al. (1996). "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". J. Biol. Chem. 271 (29): 17476–84. doi:10.1074/jbc.271.29.17476. PMID 8663391.
- Burstein ES, Spalding TA, Brann MR (1998). "The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling". J. Biol. Chem. 273 (38): 24322–7. doi:10.1074/jbc.273.38.24322. PMID 9733718.
- Sato KZ, Fujii T, Watanabe Y, et al. (1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines". Neurosci. Lett. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173.
- Wang H, Han H, Zhang L, et al. (2001). "Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart". Mol. Pharmacol. 59 (5): 1029–36. PMID 11306684.
- Buchli R, Ndoye A, Arredondo J, et al. (2002). "Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes". Mol. Cell. Biochem. 228 (1–2): 57–72. doi:10.1023/A:1013368509855. PMID 11855742.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Fujii T, Watanabe Y, Inoue T, Kawashima K (2003). "Upregulation of mRNA encoding the M5 muscarinic acetylcholine receptor in human T- and B-lymphocytes during immunological responses". Neurochem. Res. 28 (3–4): 423–9. doi:10.1023/A:1022840416292. PMID 12675126.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- De Luca V, Wang H, Squassina A, et al. (2004). "Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia". Neuropsychobiology. 50 (2): 124–7. doi:10.1159/000079102. PMID 15292665.
- Qu J, Zhou X, Xie R, et al. (2006). "The presence of m1 to m5 receptors in human sclera: evidence of the sclera as a potential site of action for muscarinic receptor antagonists". Curr. Eye Res. 31 (7–8): 587–97. doi:10.1080/02713680600770609. PMID 16877267.
- Anney RJ, Lotfi-Miri M, Olsson CA, et al. (2007). "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 Genet. 8: 46. doi:10.1186/1471-2156-8-46. PMC 1978498. PMID 17608938.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.