Journal article

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

Abstract

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-(..

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Grants

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


Funding Acknowledgements

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.