Swanson K L, Aronstam R S, Wonnacott S, Rapoport H, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
J Pharmacol Exp Ther. 1991 Oct;259(1):377-86.
Anatoxin analogs were designed to evaluate the importance of H-bonding, planarity, size and steric configuration of the anatoxin side chain moiety with regard to nicotinic potency and efficacy. This report examines the actions of these analogs on the somatic nicotinic acetylcholine receptor at two different loci: the agonist recognition site and the ion channel site. Agonist effects were evaluated using stimulation of contracture and radioligand binding competition for [125I]alpha bungarotoxin sites in Rana pipiens muscle, and stimulation of [3H]perhydrohistrionicotoxin binding and competition for [125I]alpha bungarotoxin sites in Torpedo californica electric organ. Antagonist effects were evident in the inhibition of neurally evoked twitch of the frog sciatic nerve-sartorius muscle preparation and in inhibition of [3H]perhydrohistrionicotoxin binding to Torpedo receptors. The affinity of these analogs for the agonist locus was consistently associated with activation of the AChR. Our results show that side chain steric configuration has an important role in affinity of the (+)-anatoxin-a analogs for the nicotinic acetylcholine receptor ion channel sites. Several analogs also revealed stereospecific noncompetitive actions. The (+)-anatoxin-a-related structures are important probes for characterizing both agonist and ion channel target sites on the peripheral nicotinic receptor.
设计了anatoxin类似物，以评估anatoxin侧链部分的氢键、平面性、大小和空间构型对烟碱效力和功效的重要性。本报告研究了这些类似物在两个不同位点对体细胞烟碱型乙酰胆碱受体的作用：激动剂识别位点和离子通道位点。使用刺激挛缩和对牛蛙肌肉中[125I]α-银环蛇毒素位点的放射性配体结合竞争，以及刺激加州电鳐电器官中[3H]全氢组氨毒素结合和对[125I]α-银环蛇毒素位点的竞争来评估激动剂效应。拮抗剂效应在抑制青蛙坐骨神经-缝匠肌标本的神经诱发抽搐以及抑制[3H]全氢组氨毒素与电鳐受体的结合中明显可见。这些类似物对激动剂位点的亲和力始终与乙酰胆碱受体的激活相关。我们的结果表明，侧链空间构型对（+）-anatoxin-a类似物与烟碱型乙酰胆碱受体离子通道位点的亲和力具有重要作用。几种类似物还显示出立体特异性非竞争性作用。（+）-anatoxin-a相关结构是表征外周烟碱受体上激动剂和离子通道靶位点的重要探针。
