A-85380: α4β2神经元烟碱乙酰胆碱受体临床前和临床研究的药理探针

Lynne E. Rueter, Diana L. Donnelly-Roberts, Peter Curzon, Clark A. Briggs, David J. Anderson, Robert S. Bitner
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引用次数: 38

摘要

a -85380 [3-(2(s)-偶氮基甲氧基)吡啶]是一种神经元烟碱乙酰胆碱受体(nAChR)激动剂,在临床前和临床研究中都是研究nAChR功能的有用工具。在nAChR亚型中,A-85380对α4β2和α7或α1β1δγ nAChR具有选择性。在功能性的体外阳离子通量测定中,a -85380是一种有效的、充分的激动剂。a -85380具有广谱镇痛作用,对急性、持续性和神经性疼痛模型有效。通过选择性nAChR拮抗剂或α4反义,α4β2 nAChR介导了A-85380的镇痛作用。有趣的是,作用部位取决于疼痛的类型,因为抗痛觉是通过下行抑制进入脊髓介导的,而神经性疼痛的抗异常性痛是在中枢和外周部位介导的。已开发出放射性标记形式的A-85380,并证明可安全用于人体内。在使用正电子和光子发射断层扫描的临床研究中,在帕金森病和阿尔茨海默病患者中发现α4β2 nachr明显减少。a -85380虽然没有作为治疗剂开发,但已被证明是开发用于治疗疼痛和其他疾病的新型nAChR配体的重要组成部分。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A-85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α4β2 Neuronal Nicotinic Acetylcholine Receptor

A-85380 [3-(2(s)-azetidinylmethoxy) pyridine] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist that has been a useful tool in the investigation of the function of nAChRs in both preclinical and clinical studies. Amongst nAChR subtypes, A-85380 shows selectivity for the α4β2 vs. the α7 or α1β1δγ nAChRs. In functional in vitro cation flux assays, A-85380 is a potent and full agonist. A-85380 has a broad-spectrum analgesic profile with efficacy in acute, persistent, and neuropathic pain models. As demonstrated using selective nAChR antagonists or α4 antisense, the α4β2 nAChR mediates the analgesic effects of A-85380. Interestingly, the site of action depends upon the type of pain as antinociception is mediated by descending inhibition into the spinal cord whereas anti-allodynia in neuropathic pain is mediated at both central and peripheral sites. Radiolabelled forms of A-85380 have been developed and shown to be safe for use in vivo in humans. In clinical studies using positron and photon emission tomography, marked decreases in α4β2 nAChRs have been seen in patients with Parkinson's and Alzheimer's disease. Although not developed as a therapeutic agent, A-85380 has proven to be an important component in the development of novel nAChR ligands for the treatment of pain and other disorders.

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