Epibatidine is a potent analgetic agent with very high affinity for brain nicotinic acetylcholine receptors (nAChR). We determined the activity profiles of three epibatidine derivatives, RTI-36, RTI-76, and RTI-102, which have affinity for brain nAChR equivalent to that of epibatidine but reduced analgetic activity. RNAs coding for nAChR monomeric subunits and/or concatamers were injected into Xenopus oocytes to obtain receptors of defined subunit composition and stoichiometry. The epibatidine analogs produced protracted activation of high sensitivity (HS) α4- and α2-containing receptors with the stoichiometry of 2alpha:3beta subunits but not low sensitivity (LS) receptors with the reverse ratio of alpha and beta subunits. Although not strongly activated by the epibatidine analogs, LS α4- and α2-containing receptors were potently desensitized by the epibatidine analogs. In general, the responses of α4(2)β2(2)α5 and β3α4β2α6β2 receptors were similar to those of the HS α4β2 receptors. RTI-36, the analog closest in structure to epibatidine, was the most efficacious of the three compounds, also effectively activating α7 and α3β4 receptors, albeit with lower potency and less desensitizing effect. Although not the most efficacious agonist, RTI-76 was the most potent desensitizer of α4- and α2-containing receptors. RTI-102, a strong partial agonist for HS α4β2 receptors, was effectively an antagonist for LS α4β2 receptors. Our results highlight the importance of subunit stoichiometry and the presence or absence of specific accessory subunits for determining the activity of these drugs on brain nAChR, affecting the interpretation of in vivo studies since in most cases these structural details are not known.

中文翻译：

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烟碱乙酰胆碱受体附属亚基确定依巴替丁衍生物的活性谱。

Epibatidine 是一种强效镇痛剂，对脑烟碱乙酰胆碱受体 (nAChR) 具有非常高的亲和力。我们确定了三种表巴替丁衍生物 RTI-36、RTI-76 和 RTI-102 的活性谱，它们对脑 nAChR 的亲和力与表巴替丁相当，但镇痛活性降低。将编码 nAChR 单体亚基和/或串联体的 RNA 注射到非洲爪蟾卵母细胞中，以获得具有确定亚基组成和化学计量的受体。表巴替丁类似物产生高灵敏度 (HS) α 4- 和α 的长期激活含有 2 的受体具有 2alpha:3beta 亚基的化学计量，但不是具有 alpha 和 beta 亚基反向比例的低灵敏度 (LS) 受体。虽然没有被表巴替丁类似物强烈激活，但含有LS α 4 和α 2 的受体被表巴替丁类似物有效地脱敏。一般来说，α 4(2) β 2(2) α 5 和β 3 α 4 β 2 α 6 β 2 受体的反应与HS α 4 β 的反应相似。2个受体。RTI-36 是结构与表巴替丁最接近的类似物，是三种化合物中最有效的，也能有效激活α 7 和α 3 β 4 受体，尽管效力较低且脱敏作用较小。尽管不是最有效的激动剂，RTI-76 是最有效的α 4 和α 2 受体脱敏剂。RTI-102 是 HS α 4 β 2 受体的强部分激动剂，是有效的 LS α 4 β拮抗剂2个受体。我们的结果强调了亚基化学计量和特定辅助亚基的存在与否对于确定这些药物对脑 nAChR 的活性的重要性，影响了体内研究的解释，因为在大多数情况下这些结构细节是未知的。