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  2. 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

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

  • Eur J Med Chem. 2022 Aug 27;243:114716. doi: 10.1016/j.ejmech.2022.114716.
Yoshihito Kasanami 1 Chihiro Ishikawa 2 Takahiro Kino 1 Momoka Chonan 3 Naoki Toyooka 4 Yasuhiro Takashima 1 Yuriko Iba 1 Fumiko Sekiguchi 1 Maho Tsubota 1 Tsuyako Ohkubo 5 Shigeru Yoshida 6 Atsushi Kawase 7 Takuya Okada 8 Atsufumi Kawabata 9
Affiliations

Affiliations

  • 1 Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan.
  • 2 Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan.
  • 3 Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan.
  • 4 Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan; Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan. Electronic address: toyooka@eng.u-toyama.ac.jp.
  • 5 Division of Basic Medical Sciences and Fundamental Nursing, Fukuoka Nursing College, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193, Japan.
  • 6 Department of Life Science, Faculty of Science and Engineering, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan.
  • 7 Laboratory of Biopharmaceutics, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan.
  • 8 Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan; Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama, 930-8555, Japan. Electronic address: tokada@eng.u-toyama.ac.jp.
  • 9 Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan. Electronic address: kawabata@phar.kindai.ac.jp.
Abstract

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.

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