Discovery of pimozide derivatives as novel T-type calcium channel inhibitors with little binding affinity to dopamine D < sub > 2 < /sub > receptors for treatment of somatic and visceral pain

Eur J Med Chem. 2022 Aug 27;243:114716. doi: 10.1016/j.ejmech.2022.114716. Online ahead of print.ABSTRACTT-type Ca2+ channels (T-channels), particularly Cav3.2 and Cav3.1 isoforms, are promising targets for treating various diseases including intractable pain. Given the potent inhibitory activity of pimozide, an antipsychotic, against T-channels, we conducted structure-activity relationship studies of pimozide derivatives, and identified several compounds including 3a, 3s, and 4 that had potency comparable to that of pimozide in inhibiting T-channels, but little binding affinity to dopamine D2 receptors. The introduction of a phenylbutyl group on the benzoimidazole nuclei of pimozide was considered a key structural modification to reduce the binding affinity to D2 receptors. Those pimozide derivatives potently suppressed T-channel-dependent somatic and visceral pain in mice, without causing any motor dysfunctions attributable to D2 receptor blockade, including catalepsy. The present study thus provides an avenue to develop novel selective T-channel inhibitors available for pain management via the structural modification of existing medicines.PMID:36075145 | DOI:10.1016/j.ejmech.2022.114716

Source: European Journal of Medicinal Chemistry - September 8, 2022 Category: Chemistry Authors: Yoshihito Kasanami Chihiro Ishikawa Takahiro Kino Momoka Chonan Naoki Toyooka Yasuhiro Takashima Yuriko Iba Fumiko Sekiguchi Maho Tsubota Tsuyako Ohkubo Shigeru Yoshida Atsushi Kawase Takuya Okada Atsufumi Kawabata Source Type: research