Discovery of pimozide derivatives as novel T-type calcium channel inhibitors with little binding affinity to dopamine D2 receptors for treatment of somatic and visceral pain

• Published in: European journal of medicinal chemistry Vol. 243; p. 114716
• Main Authors: Kasanami, Yoshihito, Ishikawa, Chihiro, Kino, Takahiro, Chonan, Momoka, Toyooka, Naoki, Takashima, Yasuhiro, Iba, Yuriko, Sekiguchi, Fumiko, Tsubota, Maho, Ohkubo, Tsuyako, Yoshida, Shigeru, Kawase, Atsushi, Okada, Takuya, Kawabata, Atsufumi
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05.12.2022
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114716

T-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. [Display omitted] •We developed the novel pimozide derivatives, 3a, 3s, and 4, that exhibited potent inhibitory activity against Cav3.2 T-type Ca2+ channels but little binding affinity to D2 receptors.•3a and 3s strongly suppressed Cav3.2-dependent somatic and visceral pain in mice, without causing any motor dysfunctions attributable to D2 receptor blockade.•3a, 3s, and 4 are considered promising candidates to treat intractable pain.