AID 624103 - PubChem BioAssay Summary

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Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: P. Jeffrey Conn, Vanderbilt University School of Medicine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: MH077606-01
Grant Proposal PI: P. Jeffrey Conn, Vanderbilt University School of Medicine
External Assay ID: CHRM5_AG_SUMMARY

Name: Summary of the probe development efforts to identify agonists of the human cholinergic receptor, muscarinic 1 (CHRM5).

Description:

To date, five muscarinic acetylcholine receptor (mAChR) subtypes have been identified (M1-M5) and play important roles in mediating the actions of ACh in the peripheral and central nervous systems (1-5). Of these, M1 and M4 are the most heavily expressed in the CNS and represent attractive therapeutic targets for cognition, Alzheimer's disease, and schizophrenia (6, 7). In contrast, the adverse effects of cholinergic agents are thought to be primarily due to activation of peripheral M2 and M3 mAChRs. Due to the high sequence homology and conservation of the orthosteric ACh binding site among the mAChR subtypes, development of chemical agents that are selective for a single subtype has been largely unsuccessful, and in the absence of highly selective activators of M4, it has been impossible to test the role of selective M4 activation (8). Numerous pharmacological studies have provided evidence for a diversity of mAChR subtypes in brain and other tissues (4, 5, 9). These molecularly distinct receptors have important differences, including preferential coupling to various effector systems (see (4, 5) for reviews). In general, it is thought that coupling to Gq and phospholipase C is the predominant effector system coupled to M1, M3, and M5, whereas M2 and M4 most often couple to Gi/Go and inhibition of adenylyl cyclase or ion channels.

Clinical trials with xanomeline, a M1/M4-preferring orthosteric agonist, which also has sub-micromolar activity toward M5, demonstrated efficacy as both a cognition-enhancing agent and an antipsychotic agent. In follow-up studies in rats, xanomeline displayed an antipsychotic-like profile comparable to clozapine. However, a long standing question concerned whether or not the antipsychotic efficacy or antipsychotic-like activity in animal models is mediated by activation of M1, M4, or a combination of both receptors. In addition, xanomeline has been associated with unwanted gastrointestinal side effects and syncope that resulted in patient non-compliance during the trials (10). Data from mAChR knockout mice led to the suggestion that a selective M1 agonist would be beneficial for cognition, whereas an M4 agonist would provide antipsychotic activity for the treatment of schizophrenia. This proposal is further supported by recent studies demonstrating that M4 receptors modulate the dynamics of cholinergic and dopaminergic neurotransmission and that loss of M4 function results in a state of dopamine hyperfunction. These data, coupled with findings that schizophrenic patients have altered hippocampal M4 but not M1 receptor expression, suggest that selective activators of M4 may provide a novel treatment strategy for schizophrenia patients. However, multiple studies suggest that M1 may also play an important role in the antipsychotic effects of mAChR agonists and that the relative contributions of M1 and M4 to the antipsychotic efficacy of xanomeline or antipsychotic-like effects of this compound in animal models are not known. However, highly selective centrally penetrant activators of either M1 or M4 have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. Further, in vivo active tool compounds for the M5 receptor are also unavailable. These tools will prove invaluable for verifying that novel M1 or M4 compounds do not have off target effects on M5 in vivo and assist with determining the role of M5 in the CNS.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of identify agonists, PAMs, and antagonists of the human cholinergic receptor, muscarinic 5 (CHRM5). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Bonner, T.I., N.J. Buckley, A.C. Young, and M.R. Brann, Identification of a family of muscarinic acetylcholine receptor genes. Science, 1987. 237(4814): p. 527-32.
2. Bonner, T.I., A.C. Young, M.R. Brann, and N.J. Buckley, Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron, 1988. 1(5): p. 403-10.
3. Peralta, E.G., A. Ashkenazi, J.W. Winslow, D.H. Smith, J. Ramachandran, and D.J. Capon, Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. Embo J, 1987. 6(13): p. 3923-9.
4. Caulfield, M.P., Muscarinic receptors--characterization, coupling and function. Pharmacol Ther, 1993. 58(3): p. 319-79.
5. Hulme, E.C., N.J. Birdsall, and N.J. Buckley, Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol, 1990. 30: p. 633-73.
6. Levey, A.I., S.M. Edmunds, V. Koliatsos, R.G. Wiley, and C.J. Heilman, Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation. J Neurosci, 1995. 15(5 Pt 2): p. 4077-92.
7. Jakubik, J., P. Michal, E. Machova, and V. Dolezal, Importance and prospects for design of selective muscarinic agonists. Physiol Res, 2008. 57 Suppl 3: p. S39-47.
8. Conn, P.J., C.K. Jones, and C.W. Lindsley, Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders. Trends Pharmacol Sci, 2009. 30(3): p. 148-55.
9. Waelbroeck, M., M. Tastenoy, J. Camus, and J. Christophe, Binding of selective antagonists to four muscarinic receptors (M1 to M4) in rat forebrain. Mol Pharmacol, 1990. 38(2): p. 267-73.
10. Bodick, N.C., W.W. Offen, A.I. Levey, N.R. Cutler, S.G. Gauthier, A. Satlin, H.E. Shannon, G.D. Tollefson, K. Rasmussen, F.P. Bymaster, D.J. Hurley, W.Z. Potter, and S.M. Paul, Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol, 1997. 54(4): p. 465-73.

Keywords:

Summary, Summary AID, CHRM5, HM5, M5R, M5, mAChR, cholinergic receptor, muscarinic 5, primary, singlicate, cell-based, CHO, GPCR, receptor, acetylcholine, cholinergic, cholinergic receptor, acetylcholine receptor, muscarinic, allosteric, positive, agonist, calcium, dye, Fluo8, FLINT, fluorescence, fluor, activate, activator, activation, antagonist, CNS, brain, central nervous system, mood, psychosis, dementia, Parkinson's, Lewy body dementia, rat, vascular dementia, schizophrenia, HTS, high throughput screen, 1536, Scripps, Scripps Florida, MLSMR, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.