Many synthetic compounds to which we attribute specific activities are produced as racemic mixtures of stereoisomers, and it may be that all the desired activity comes from a single enantiomer. We have previously shown this to be the case with the α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS) and the α7 ago-PAM 4BP-TQS. Cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-te-trahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (2,3,5,6TMP-TQS), previously published as a “silent allosteric modulator” and an antagonist of α7 allosteric activation, shares the same scaffold with three chiral centers as the aforementioned compounds. We isolated the enantiomers of 2,3,5,6TMP-TQS and determined that the (−) isomer was a significantly better antagonist than the (+) isomer of the allosteric activation of both wild-type α7 and the nonorthosterically activatible C190A α7 mutant by the ago-PAM GAT107 (the active isomer of 4BP-TQS). In contrast, (+)2,3,5,6TMP-TQS proved to be an α7 PAM. (−)2,3,5,6TMP-TQS was shown to antagonize the allosteric activation of α7 by the structurally unrelated ago-PAM B-973B as well as the allosteric activation of the TQS-sensitive α4β2L15′M mutant. In silico docking of 2,3,5,6TMP-TQS in the putative allosteric activation binding site suggested a specific interaction of the (−) enantiomer with α7T106, and allosteric activation of α7T106 mutants was not inhibited by (−)2,3,5,6TMP-TQS, confirming the importance of this interaction and supporting the model of the allosteric binding site. Comparisons and contrasts between 2,3,5,6TMP-TQS isomers and active and inactive enantiomers of other TQS-related compounds identify the orientation of the cyclopentenyl ring to the plane of the core quinoline to be a crucial determinate of PAM activity.

中文翻译：

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2,3,5,6TMP-TQS（一种假定的 α7 nAChR 沉默变构调节剂）立体异构体的不同活性特征。


许多我们赋予特定活性的合成化合物都是作为立体异构体的外消旋混合物生产的，并且所有所需的活性可能都来自单一对映体。我们之前已经证明α 7 烟碱乙酰胆碱受体正变构调节剂（PAM）3a,4,5,9b-四氢-4-(1-萘基)-3H-环戊烷[c]喹啉-8-就是这种情况磺酰胺 (TQS) 和α 7 ago-PAM 4BP-TQS。顺式-反式-4-(2,3,5,6-四甲基苯基)-3a,4,5,9b-四氢-3H-环戊[c]喹啉-8-磺酰胺(2,3,5,6TMP- TQS）之前发表为“沉默变构调节剂”和α 7 变构激活拮抗剂，与上述化合物共享具有三个手性中心的相同支架。我们分离了 2,3,5,6TMP-TQS 的对映体，并确定 (-) 异构体是比 (+) 异构体明显更好的野生型α 7 和非正构激活 C190A α变构激活拮抗剂ago-PAM GAT107（4BP-TQS 的活性异构体）的 7 突变体。相反，(+)2,3,5,6TMP-TQS 被证明是α 7 PAM。 (−)2,3,5,6TMP-TQS 显示可拮抗结构上不相关的 ago-PAM B-973B 对α 7 的变构激活以及 TQS 敏感的α 4 β 2L15'M 突变体的变构激活。在推定的变构激活结合位点中 2,3,5,6TMP-TQS 的计算机对接表明 (−) 对映异构体与α 7T106 存在特异性相互作用，并且α 7T106 突变体的变构激活不受 (−)2 抑制， 3,5,6TMP-TQS，证实了这种相互作用的重要性并支持变构结合位点的模型。 2,3,5,6TMP-TQS 异构体与其他 TQS 相关化合物的活性和非活性对映体之间的比较和对比表明，环戊烯基环相对于核心喹啉平面的方向是 PAM 活性的关键决定因素。