Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism.

Sheffler DJ, Sevel C, Le U, Lovell KM, Tarr JC, Carrington SJ, Cho HP, Digby GJ, Niswender CM, Conn PJ, Hopkins CR, Wood MR, Lindsley CW
Bioorg Med Chem Lett. 2013 23 (1): 223-7

PMID: 23200253 · PMCID: PMC3525729 · DOI:10.1016/j.bmcl.2012.10.132

This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism.

Copyright © 2012 Elsevier Ltd. All rights reserved.

MeSH Terms (17)

Acetylcholine Allosteric Regulation Allosteric Site Animals Benzamides Benzimidazoles Calcium CHO Cells Cricetinae Cricetulus Humans Piperidines Rats Receptor, Muscarinic M1 Receptors, Muscarinic Structure-Activity Relationship Transfection

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