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

共 50 条

[21] PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor disorder associated with neuropathic pain model
Sun, Zhihong
Meng, Ping
Su, Chunyu
Ji, Shengmin
Gao, Yonglin
Wang, Hongbo
Tian, Jingwei
Li, Chunmei
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2021, 429
[22] INCB38579, a novel and potent histamine H4 receptor small molecule antagonist with anti-inflammatory pain and anti-pruritic functions
Shin, Niu
Covington, Maryanne
Bian, Di
Zhuo, Jincong
Bowman, Kevin
Li, Yanlong
Soloviev, Maxim
Qian, Ding-Quan
Feldman, Patricia
Leffet, Lynn
He, Xin
Wang, Kathy He
Krug, Kristin
Bell, Dan
Czerniak, Philip
Hu, Zhijing
Zhao, Hui
Zhang, Jing
Yeleswaram, Swamy
Yao, Wenqing
Newton, Robert
Scherle, Peggy
EUROPEAN JOURNAL OF PHARMACOLOGY, 2012, 675 (1-3) : 47 - 56
[23] Novel strategies for the treatment of migraine attacks via the CGRP, serotonin, dopamine, PAC1, and NMDA receptors
Tajti, Janos
Csati, Anett
Vecsei, Laszlo
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2014, 10 (11) : 1509 - 1520
[24] Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain
Hossain, Mohammad Zakir
Ando, Hiroshi
Unno, Shumpei
Kitagawa, Junichi
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2020, 21 (04)
[25] CHARACTERIZATION OF A NOVEL AND POTENT 5-HYDROXYTRYPTAMINE1A RECEPTOR ANTAGONIST
LIAU, LM
SLEIGHT, AJ
PITHA, J
PEROUTKA, SJ
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1991, 38 (03) : 555 - 559
[26] Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice
Vang, Derek
Paul, Jinny A.
Nguyen, Julia
Tran, Huy
Vincent, Lucile
Yasuda, Dennis
Zaveri, Nurulain T.
Gupta, Kalpna
HAEMATOLOGICA, 2015, 100 (12) : 1517 - 1525
[27] Novel hybrid compounds, opioid agonist plus melanocortin 4 receptor antagonist, as efficient analgesics in mouse chronic constriction injury model of neuropathic pain
Starnowska-Sokol, Joanna
Piotrowska, Anna
Bogacka, Joanna
Makuch, Wioletta
Mika, Joanna
Witkowska, Ewa
Godlewska, Magda
Osiejuk, Jowita
Gatarz, Sandra
Misicka, Aleksandra
Przewlocka, Barbara
NEUROPHARMACOLOGY, 2020, 178
[28] Small-molecule CaVα1•CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking
Chen, Xingjuan
Liu, Degang
Zhou, Donghui
Si, Yubing
Xu, David
Stamatkin, Christopher W.
Ghozayel, Mona K.
Ripsch, Matthew S.
Obukhov, Alexander G.
White, Fletcher A.
Meroueh, Samy O.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (45) : E10566 - E10575
[29] MPZP:: A novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist
Richardson, Heather N.
Zhao, Yu
Fekete, Eva M.
Funk, Cindy K.
Wirsching, Peter
Janda, Kim D.
Zorrilla, Eric P.
Koob, George F.
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2008, 88 (04) : 497 - 510
[30] Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature
Kamp, Jasper
Van Velzen, Monique
Olofsen, Erik
Boon, Martijn
Dahan, Albert
Niesters, Marieke
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2019, 15 (12) : 1033 - 1041

← 1 2 3 4 5 →