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

Ichiro Takasaki; Haruna Ogashi; Takuya Okada; Ayaka Shimodaira; Daichi Hayakawa; Ai Watanabe; Atsuro Miyata; Takashi Kurihara; Hiroaki Gouda; Naoki Toyooka

doi:10.1016/j.ejmech.2019.111902

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. Epub 2019 Nov 19.

Authors

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.

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology*
Animals
Behavior, Animal / drug effects
Dose-Response Relationship, Drug
Male
Mice
Mice, Inbred Strains
Molecular Structure
Neuralgia / drug therapy*
Neuralgia / metabolism
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / antagonists & inhibitors*
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Analgesics
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Small Molecule Libraries