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
  • 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: [email protected].
  • 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: [email protected].
  • 9. Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan. Electronic address: [email protected].
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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