2. Academic Validation
  3. 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.
PMID: 36075145 DOI: 10.1016/j.ejmech.2022.114716
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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