RESUMO
This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism.
Assuntos
Receptor Muscarínico M1/agonistas , Acetilcolina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Humanos , Piperidinas/química , Piperidinas/farmacologia , Ratos , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo , Receptores Muscarínicos/química , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 µM and is inactive against mGlu(5).
