Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain.
Basic Information
ID: ALA4680128
Journal: Eur J Med Chem
Title: Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain.
Authors: Takasaki I,Ogashi H,Okada T,Shimodaira A,Hayakawa D,Watanabe A,Miyata A,Kurihara T,Gouda H,Toyooka N
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.
CiteXplore: 31771828
DOI: 10.1016/j.ejmech.2019.111902
Patent ID: ┄