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 (αß), and direct agonist properties (τB).
Subject(s)
Cholinergic Agonists/chemical synthesis , Cholinergic Agonists/pharmacology , Receptor, Muscarinic M4/metabolism , Thienopyridines/chemical synthesis , Thienopyridines/pharmacology , Acetylcholine/metabolism , Allosteric Regulation , Allosteric Site/drug effects , Animals , CHO Cells , Cholinergic Agonists/chemistry , Cricetulus , Drug Evaluation , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Structure , Phosphorylation , Thienopyridines/chemistryABSTRACT
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 (αß), and direct agonist properties (τB).
