RESUMO
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).
Assuntos
Agonistas Colinérgicos/síntese química , Agonistas Colinérgicos/farmacologia , Receptor Muscarínico M4/metabolismo , Tienopiridinas/síntese química , Tienopiridinas/farmacologia , Acetilcolina/metabolismo , Regulação Alostérica , Sítio Alostérico/efeitos dos fármacos , Animais , Células CHO , Agonistas Colinérgicos/química , Cricetulus , Avaliação de Medicamentos , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Fosforilação , Tienopiridinas/químicaRESUMO
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).