Novel methyllycaconitine analogues selective for the α4β2 over α7 nicotinic acetylcholine receptors

Ryan Gallagher; Taima Qudah; Thomas Balle; Mary Chebib; Malcolm D McLeod

doi:10.1016/j.bmc.2021.116516

Novel methyllycaconitine analogues selective for the α4β2 over α7 nicotinic acetylcholine receptors

Bioorg Med Chem. 2021 Dec 1:51:116516. doi: 10.1016/j.bmc.2021.116516. Epub 2021 Nov 10.

Authors

Ryan Gallagher¹, Taima Qudah², Thomas Balle³, Mary Chebib³, Malcolm D McLeod⁴

Affiliations

¹ Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.
² Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia.
³ Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
⁴ Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia. Electronic address: malcolm.mcleod@anu.edu.au.

PMID: 34798380
DOI: 10.1016/j.bmc.2021.116516

Abstract

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)₃(β2)₂ over (α4)₂(β2)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 α4β2 nAChR subtype.

Keywords: Alpha4beta2; Ligand-gated ion channel; Methyllycaconitine; Nicotinic acetylcholine receptor; Noncompetitive antagonist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aconitine / analogs & derivatives
Aconitine / chemical synthesis
Aconitine / chemistry
Animals
Dose-Response Relationship, Drug
Molecular Structure
Oocytes / drug effects
Oocytes / metabolism
Receptors, Nicotinic / metabolism*
Structure-Activity Relationship
Xenopus laevis
alpha7 Nicotinic Acetylcholine Receptor / antagonists & inhibitors*
alpha7 Nicotinic Acetylcholine Receptor / metabolism

Substances

Receptors, Nicotinic
alpha7 Nicotinic Acetylcholine Receptor
nicotinic receptor alpha4beta2
methyllycaconitine
Aconitine