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

Abstract 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.