Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors

Ashraf M A Qasem; Michael G Rowan; Victoria R Sanders; Neil S Millar; Ian S Blagbrough

doi:10.1021/acsbiomedchemau.2c00057

Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors

ACS Bio Med Chem Au. 2023 Feb 14;3(2):147-157. doi: 10.1021/acsbiomedchemau.2c00057. eCollection 2023 Apr 19.

Authors

Ashraf M A Qasem¹, Michael G Rowan¹, Victoria R Sanders², Neil S Millar², Ian S Blagbrough¹

Affiliations

¹ School of Pharmacy, University of Bath, Bath BA2 7AY, U.K.
² Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, U.K.

Abstract

Methyllycaconitine (MLA), 1, is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC₅₀ = 2 nM) selective antagonist of α7 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 α7 nAChRs and compared to that of MLA 1. The most efficacious analogue (16) reduced α7 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 α7 nAChRs but also indicates that further optimization may be possible to achieve antagonist activity comparable to that of MLA 1.