Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.
Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia.
Bioorg Med Chem. 2021 Dec 1;51:116516. doi: 10.1016/j.bmc.2021.116516. Epub 2021 Nov 10.
Analogues of methyllycaconitine (MLA) based on a (3-ethyl-9-methylidene-3-azabicyclo[3.3.1]nonan-1-yl)methanol template have been designed and synthesised that incorporate the modified ester sidechains distinct from that present in the natural product. Electrophysiology experiments using Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) revealed selected analogues served as non-competitive inhibitors that showed selectivity for the α4β2 over α7 nAChR subtypes, and selectivity for the (α4)(β2) over (α4)(β2) stoichiometry. This study more clearly defines the biological effects of MLA analogues and identifies strategies for the development of MLA analogues as selective ligands for the α4β2 nAChR subtype.
基于（3-乙基-9-亚甲基-3-氮杂双环[3.3.1]壬烷-1-基）甲醇模板的甲基脱氢鹰爪豆碱（MLA）类似物已被设计和合成，其包含与天然产物中存在的不同的修饰酯侧链。使用表达烟碱型乙酰胆碱受体（nAChR）的非洲爪蟾卵母细胞进行的电生理学实验表明，选定的类似物作为非竞争性抑制剂，对α4β2 型 nAChR 亚型具有选择性，并且对（α4）（β2）比（α4）（β2）计量比具有选择性。这项研究更清楚地定义了 MLA 类似物的生物学效应，并确定了将 MLA 类似物开发为α4β2 nAChR 亚型选择性配体的策略。
