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

被引：15

作者：

Takasaki, Ichiro ^{[1
,2
]}

Ogashi, Haruna ^{[3
]}

Okada, Takuya ^{[2
,3
]}

Shimodaira, Ayaka ^{[1
]}

Hayakawa, Daichi ^{[4
]}

Watanabe, Ai ^{[1
]}

Miyata, Atsuro ^{[5
]}

Kurihara, Takashi ^{[5
]}

Gouda, Hiroaki ^{[4
]}

Toyooka, Naoki ^{[2
,3
]}

机构：

[1] Univ Toyama, Grad Sch Sci & Engn, Dept Pharmacol, Toyama 9308555, Japan

[2] Univ Toyama, Grad Sch Innovat Life Sci, Toyama 9308555, Japan

[3] Univ Toyama, Grad Sch Sci & Engn, Dept Biofunct Mol Engn, Toyama 9308555, Japan

[4] Showa Univ, Sch Pharm, Dept Analyt & Phys Chem, Tokyo 1428555, Japan

[5] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Pharmacol, Kagoshima 8908544, Japan

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 186卷

关键词：

PACAP; PAC1; receptor; Small-molecule antagonist; Neuropathic pain; Allodynia; Analgesics; CYCLASE-ACTIVATING POLYPEPTIDE; ADENYLATE-CYCLASE; ALLODYNIA; MAXADILAN; MODEL;

D O I：

10.1016/j.ejmech.2019.111902

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页数：9

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