Synthesis and Biological Evaluation of Isophthalamide Derivatives as T-type Calcium Channel Blockers

摘要

Since mibefradil, a selective T-type calcium channel blocker, was withdrawn from the market in 1998 due to drug-drug interaction, there have been efforts to discover novel T-type calcium blockers. Mibefradil had been approved for the treatment of angina pectoris and hypertension by the FDA in 1997. According to accumulation of new findings on T-type calcium channels, it has been reported that T-type calcium channels play crucial roles in the control of pain which are caused by hyperexitable neurons. The role of T-type calcium channels in pain has been addressed using specific genetic modulation of T-type calcium channel isoforms. In the case of Cav3.1 knockout (α_(1G)~(-/-)) mice, it was observed that, after L5 spinal nerve ligation, spontaneous pain responses were reduced and a threshold for paw withdrawal was increased in response to mechanical stimulation. Cav3.2 antisense treatment resulted in major anti-nociceptive and anti-hyperalgesic effect, suggesting that Cav3.2 plays a major pronociceptive role in acute and chronic pain states. Together, the results of these two studies suggest that blocking T-type calcium channels should reduce nociceptive pain and neuropathic pain.