Methyllycaconitine (MLA), 1, is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC(50) = 2 nM) selective antagonist of alpha7 nicotinic acetylcholine receptors (nAChRs). Several structural factors affect its activity such as the neopentyl ester side-chain and the piperidine ring N-side-chain. The synthesis of simplified AE-bicyclic analogues 14-21 possessing different ester and nitrogen side-chains was achieved in three steps. The antagonist effects of synthetic analogues were examined on human alpha7 nAChRs and compared to that of MLA 1. The most efficacious analogue (16) reduced alpha7 nAChR agonist responses [1 nM acetylcholine (ACh)] to 53.2 +/- 1.9% compared to 3.4 +/- 0.2% for MLA 1. This demonstrates that simpler analogues of MLA 1 possess antagonist effects on human alpha7 nAChRs but also indicates that further optimization may be possible to achieve antagonist activity comparable to that of MLA 1. CI - (c) 2023 The Authors. Published by American Chemical Society.