Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor.
The M4 mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M4 PAMs derived from VU0152100 and VU10005. These compounds investigate the pharmacological effects of previously identified methoxy and fluoro substituents, providing useful estimates of affinity (KB), cooperativity (αβ), and direct agonist properties (τB).
Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381-399 Royal Parade, Parkville VIC 3052, Australia.
Tracey
T
Huynh
Celine
C
Valant
Ian T
IT
Crosby
Patrick M
PM
Sexton
Arthur
A
Christopoulos
Ben
B
Capuano
D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D043588:Receptor, Muscarinic M4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C579414:3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno(2,3-b)pyridine-2-carboxamide; D011725:Pyridines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine