European Journal of Medicinal Chemistry (2020)
Update date:2022-08-11
Topics:
Takasaki, Ichiro
Ogashi, Haruna
Okada, Takuya
Shimodaira, Ayaka
Hayakawa, Daichi
Watanabe, Ai
Miyata, Atsuro
Kurihara, Takashi
Gouda, Hiroaki
Toyooka, Naoki
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.
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