2. Academic Validation
  3. Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain

Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain

  • Eur J Med Chem. 2020 Jan 15;186:111902. doi: 10.1016/j.ejmech.2019.111902.
Ichiro Takasaki 1,  Haruna Ogashi 2,  Takuya Okada 3,  Ayaka Shimodaira 4,  Daichi Hayakawa 5,  Ai Watanabe 4,  Atsuro Miyata 6,  Takashi Kurihara 6,  Hiroaki Gouda 5,  Naoki Toyooka 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, Toyama, 930-8555, Japan; Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, 930-8555, Japan. Electronic address: takasaki@eng.u-toyama.ac.jp.
  • 2 Department of Bio-functional Molecular Engineering, Graduate School of Science and Engineering, University of Toyama, Toyama, 930-8555, Japan.
  • 3 Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, 930-8555, Japan; Department of Bio-functional Molecular Engineering, Graduate School of Science and Engineering, University of Toyama, Toyama, 930-8555, Japan.
  • 4 Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, Toyama, 930-8555, Japan.
  • 5 Department of Analytical and Physical Chemistry, School of Pharmacy, Showa University, Tokyo, 142-8555, Japan.
  • 6 Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8544, Japan.
  • 7 Graduate School of Innovative Life Science, University of Toyama, Toyama, 930-0194, 930-8555, Japan; Department of Bio-functional Molecular Engineering, Graduate School of Science and Engineering, University of Toyama, Toyama, 930-8555, Japan. Electronic address: toyooka@eng.u-toyama.ac.jp.
PMID: 31771828 DOI: 10.1016/j.ejmech.2019.111902
Abstract

We recently identified novel small-molecule antagonists of the PACAP type I (PAC1) receptor using docking-based in silico screening followed by in vitro/vivo pharmacological assays. In the present study, we synthesized 18 novel derivatives based on the structure of PA-9, a recently developed antagonist of the PAC1 receptor, with a view to obtain a panel of compounds with more potent antagonistic and analgesic activities. Among them, compound 3d showed improved antagonistic activities. Intrathecal injection of 3d inhibited both pituitary adenylate cyclase-activating polypeptide (PACAP) and spinal nerve ligation-induced mechanical allodynia. The effects were more potent than PA-9. Compound 3d also showed anti-allodynic effects following oral administration. Hence, our results suggest that 3d may become an orally available analgesic in the treatment of the neuropathic pain.

Keywords

Allodynia; Analgesics; Neuropathic pain; PAC1 receptor; PACAP; Small-molecule antagonist.

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