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 alpha4beta2 over alpha7 nAChR subtypes, and selectivity for the (alpha4)(3)(beta2)(2) over (alpha4)(2)(beta2)(3) 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 alpha4beta2 nAChR subtype. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved.