Probing the binding site of novel selective positive allosteric modulators at the M-1 muscarinic acetylcholine receptor
Elham Khajehali, Celine Valant, Manuela Jorg, Andrew B Tobin, P Jeffrey Conn, Craig W Lindsley, Patrick M Sexton, Peter J Scammells, Arthur Christopoulos
BIOCHEMICAL PHARMACOLOGY | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2018
Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(..View full abstract
Awarded by National Health and Medical Research Council (NHMRC) Program Grant
Awarded by Wellcome Trust Collaborative Research Award
Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
This work was supported by National Health and Medical Research Council (NHMRC) Program Grant (APP1055134) and Wellcome Trust Collaborative Research Award (201529/Z/16/Z). AC is a Senior Principal, and PMS a Principal, Research Fellow of the National Health and Medical Research Council of Australia. CV is supported by a Future Fellowship from the Australian Research Council.