RESUMO
While the muscarinic acetylcholine receptor mAChR subtype 5 (M5) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M5 antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 (45) showed exquisite potency (human M5 IC50 = 20 nM), good subtype selectivity (>500 fold selectivity against human M1-4), desirable brain exposure (Kp = 0.68, Kp,uu = 0.65), and high oral bioavailability (%F > 100%). VU6036864 (45) and its close analogues will support further studies of M5 as advanced antagonist tool compounds and play an important role in the emerging biology of M5.
Assuntos
Piridinas , Receptor Muscarínico M5 , Humanos , Animais , Relação Estrutura-Atividade , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Piridinas/farmacocinética , Receptor Muscarínico M5/antagonistas & inibidores , Receptor Muscarínico M5/metabolismo , Triazóis/farmacologia , Triazóis/química , Triazóis/síntese química , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/síntese química , Cricetulus , Células CHO , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) represents a novel potential target for the treatment of multiple addictive disorders, including opioid use disorder. Through chemical optimization of several functional high-throughput screening hits, VU6019650 (27b) was identified as a novel M5 orthosteric antagonist with high potency (human M5 IC50 = 36 nM), M5 subtype selectivity (>100-fold selectivity against human M1-4) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, 27b blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover, 27b also inhibited oxycodone self-administration in male Sprague-Dawley rats within a dose range that did not impair general motor output.