GeX-2(GeX-2) - 药物靶点：GABAB receptor x nAChRα9&α10_在研适应症：疼痛_专利_临床

概要

基本信息

药物类型

小分子化药

别名-

靶点

GABAB receptor x nAChRα9&α10

作用机制

GABAB receptor拮抗剂(γ-氨基丁酸B受体拮抗剂)、α9α10 receptor拮抗剂(神经性乙酰胆碱受体蛋白α9/β10复合体拮抗剂)

治疗领域

神经系统疾病

在研适应症

疼痛

非在研适应症-

原研机构

中国海洋大学

在研机构

中国海洋大学

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)临床前

特殊审评-

关联

100 项与 GeX-2 相关的临床结果

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100 项与 GeX-2 相关的转化医学

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100 项与 GeX-2 相关的专利（医药）

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1

项与 GeX-2 相关的文献（医药）

2024-10-24·Journal of Medicinal Chemistry

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor

Article

作者: Li, Xiao ; Zhou, Shenglu ; Jiang, Tao ; Wang, Shoushi ; Li, Tianmiao ; Tae, Han-Shen ; Cai, Wenqing ; Adams, David J. ; Yu, Rilei

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABA_B) receptor-coupled Ca_V2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABA_B receptor-coupled Ca_V2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatin-induced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

100 项与 GeX-2 相关的药物交易

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