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

• Published in: European journal of medicinal chemistry Vol. 186; p. 111902
• Main Authors: Takasaki, Ichiro, Ogashi, Haruna, Okada, Takuya, Shimodaira, Ayaka, Hayakawa, Daichi, Watanabe, Ai, Miyata, Atsuro, Kurihara, Takashi, Gouda, Hiroaki, Toyooka, Naoki
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.01.2020; Elsevier
• Subjects: Allodynia; Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Behavior, Animal - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred Strains; Molecular Structure; Neuralgia - drug therapy; Neuralgia - metabolism; Neuropathic pain; PAC1 receptor; PACAP; Pharmacology & Pharmacy; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - antagonists & inhibitors; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - metabolism; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Small-molecule antagonist; Structure-Activity Relationship; Allodynia; Small-molecule antagonist; PACAP; Analgesics; PAC1 receptor; Neuropathic pain; CYCLASE-ACTIVATING POLYPEPTIDE; MAXADILAN; MODEL; ADENYLATE-CYCLASE
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111902

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. [Display omitted] •A novel and potent small-molecule antagonist of PAC1 receptor was synthesized.•We identified compound 3d as a novel and potent PAC1 receptor antagonist.•Intrathecal injection of 3d inhibited PACAP- and nerve injury-induced allodynia.•Compound 3d also showed anti-allodynic effects following oral administration.