更新于：2024-11-01

nAChRα9&α10 x CHRNA7

更新于：2024-11-01

基本信息

关联

项与 nAChRα9&α10 x CHRNA7 相关的药物

MG-624

靶点

CHRNA7 x nAChRα9&α10

作用机制

α7 receptor拮抗剂 [+1]

在研机构

University of Milan

原研机构

University of Milan

在研适应症

腺癌 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 nAChRα9&α10 x CHRNA7 相关的临床结果

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100 项与 nAChRα9&α10 x CHRNA7 相关的转化医学

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0 项与 nAChRα9&α10 x CHRNA7 相关的专利（医药）

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项与 nAChRα9&α10 x CHRNA7 相关的文献（医药）

2024-06-13·Journal of Medicinal Chemistry

Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation

Article

作者: Papke, Roger L ; Horenstein, Nicole A ; Thakur, Ganesh A ; Chiang, Ka ; Richter, Katrin ; Sharma, Abhisheak ; Herz, Sara M ; Damaj, M Imad ; Kanumuri, Siva R Raju ; Andleeb, Hina ; Grau, Veronika ; Stokes, Clare

There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound 3c was 10-fold selective for α9α10 over α9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1β release in THP-1 cells. The analgesic activity of 3h was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.

2023-05-26·Marine drugs

Substitution of D-Arginine at Position 11 of α-RgIA Potently Inhibits α7 Nicotinic Acetylcholine Receptor.

Article

作者: Zhang, Junjie ; Li, Rui ; Wu, Yong ; Ren, Jie ; Zhu, Xiaopeng ; Luo, Sulan ; Zhangsun, Dongting

Conotoxins are a class of disulfide-rich peptides found in the venom of cone snails, which have attracted considerable attention in recent years due to their potent activity on ion channels and potential for therapeutics. Among them, α-conotoxin RgIA, a 13-residue peptide, has shown great promise as a potent inhibitor of α9α10 nAChRs for pain management. In this study, we investigated the effect of substituting the naturally occurring L-type arginine at position 11 of the RgIA sequence with its D-type amino acid. Our results indicate that this substitution abrogated the ability of RgIA to block α9α10 nAChRs, but instead endowed the peptide with the ability to block α7 nAChR activity. Structural analyses revealed that this substitution induced significant alteration of the secondary structure of RgIA[11r], which consequently affected its activity. Our findings underscore the potential of D-type amino acid substitution as a promising strategy for designing novel conotoxin-based ligands targeting different types of nAChRs.

2022-12-22·Journal of Medicinal Chemistry1区 · 医学

Mechanism of Action and Structure–Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor

1区 · 医学

Article

作者: Zhao, Zitong ; Tae, Han-Shen ; Li, Xiao ; Liang, Jiazhen ; Zhang, Jinghui ; Chen, Shen ; Yu, Rilei ; Jiang, Tao ; Adams, David J.

α-Conotoxins (α-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC₅₀) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(-) and α9(+)α9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC₅₀ of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.