title: 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.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Christian
authors.initials: C
authors.lastname: Sevel
authors.forename: Uyen
authors.initials: U
authors.lastname: Le
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lovell
authors.forename: James C
authors.initials: JC
authors.lastname: Tarr
authors.forename: Sheridan J S
authors.initials: SJ
authors.lastname: Carrington
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Digby
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C532626:1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one; D001549:Benzamides; D001562:Benzimidazoles; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C574616:VU0357017; D000109:Acetylcholine; D002118:Calcium