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
  • 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: [email protected].
  • 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: [email protected].
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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