Multi-Functional 3,4-Dihydroquinazoline Derivative as T-Type Calcium Channel Blocker: Pharmacokinetics and Anti-Tremor Activity

摘要

The pharmacology of T-type calcium channels is in complex because many drugs have been found to block T-type currents. Unfortunately, none of these compounds has high selectivity for these channels. Mibefradil has been marketed worldwide for the treatment of hypertension and angina for a short period before it was withdrawn due to its pharmacokinetic and pharmacodynamic interactions with some other drugs such as terfen-adine, astemizole, cisapride, cyclosporine, tricyclic antidepressants. Mibefradil binds to skeletal muscle L-type calcium channels and brain voltage-gated sodium channels with dissociation constants of 2.3 and 17 nM, respectively. It also can block potassium and chloride channels. Obviously, this makes it not an ideal tool for in vitro or in vivo studies on T-type channels. Therefore, more potent and selective blockers are required to study the fundamental function of T-type channel and the related pathophysiological diseases such as epilepsy, neuronal pain, hypertension, congestive heart failure, and cancer. Recently, our group have reported the identification of 3,4-dihydroquinazoline derivatives as a novel scaffold, which are potent and selective T-type calcium blockers. These compounds also exhibited the anti-cancer activity in vitro via cell-cycle arrest mechanism.