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

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.