title: Synthesis and pharmacological evaluation of M4 muscarinic receptor positive allosteric modulators derived from VU10004.
abstract: 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 VU10004. These compounds investigate the pharmacological effects of target thieno[2,3-b]pyridines assembled from primary cycloalkanamines and cyclic secondary amines providing useful estimates of affinity (KB), cooperativity (αβ), and direct agonist properties (τB).
authors: †Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381-399 Royal Parade, Parkville VIC 3052, Australia.
authors: Tracey
authors: T
authors: Huynh
authors: †Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381-399 Royal Parade, Parkville VIC 3052, Australia.
authors: Celine
authors: C
authors: Valant
authors: †Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381-399 Royal Parade, Parkville VIC 3052, Australia.
authors: Ian T
authors: IT
authors: Crosby
authors: †Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381-399 Royal Parade, Parkville VIC 3052, Australia.
authors: Patrick M
authors: PM
authors: Sexton
authors: †Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381-399 Royal Parade, Parkville VIC 3052, Australia.
authors: Arthur
authors: A
authors: Christopoulos
authors: †Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381-399 Royal Parade, Parkville VIC 3052, Australia.
authors: Ben
authors: B
authors: Capuano
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D018679:Cholinergic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003412:Cricetulus; D004341:Drug Evaluation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015394:Molecular Structure; D010766:Phosphorylation; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D058924:Thienopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018679:Cholinergic Agonists; D043588:Receptor, Muscarinic M4; D058924:Thienopyridines; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine
keywords: LY2033298; PAMs; Positive allosteric modulators; VU10004; muscarinic M4 receptor