Harvey Andrew J, Avery Thomas D, Schaeffer Laurent, Joseph Christophe, Huff Belinda C, Singh Rajinder, Morice Christophe, Giethlen Bruno, Grishin Anton A, Coles Carolyn J, Kolesik Peter, Wagner Stéphanie, Andriambeloson Emile, Huyard Bertrand, Poiraud Etienne, Paul Dharam, O'Connor Susan M
Bionomics Limited, 31 Dalgleish Street, Thebarton, SA-5031, Australia.
Prestwick Chemicals, 220 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67400 Illkirch, France.
ACS Med Chem Lett. 2019 Mar 25;10(5):754-760. doi: 10.1021/acsmedchemlett.9b00001. eCollection 2019 May 9.
Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (,)- () and its analogues with RR stereochemistry around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochemistry (e.g., (,)-) are Type II PAMs as measured using patch-clamp electrophysiology. Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of , a small molecule with good CNS-drug like properties and clinical candidate potential.
α7烟碱型乙酰胆碱受体（α7 nAChRs）的正变构调节剂（PAMs）对通道动力学的影响可能具有不同特性。I型PAMs可增强通道对乙酰胆碱的峰值反应，但似乎不影响通道脱敏动力学，而II型PAMs既能增加通道反应又能延迟受体脱敏。文献中均报道了I型和II型PAMs，但描述其结构-动力学特征关系的报告有限。在此，我们报告了一类新型化合物，它们具有I型或II型行为，可通过中心环丙基环周围的相对立体化学进行调节：例如，(,)- ()及其在中心环丙基环周围具有RR立体化学的类似物为I型PAMs，而使用膜片钳电生理学测量时，同一系列中具有SS立体化学的化合物（如(,)-）为II型PAMs。通过改变苯胺环上的取代基，可进一步精确控制动力学：一般来说，用强吸电子基团取代苯胺会降低这些化合物的II型特性。我们的构效关系优化工作促成了的发现，这是一种具有良好中枢神经系统药物样特性和临床候选潜力的小分子。
