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

Ryan Gallagher, Taima Qudah, Thomas Balle, Mary Chebib, Malcolm D. McLeod^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	116516
Journal	Bioorganic and Medicinal Chemistry
Volume	51
DOIs	https://doi.org/10.1016/j.bmc.2021.116516
Publication status	Published - 1 Dec 2021

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10.1016/j.bmc.2021.116516

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title = "Novel methyllycaconitine analogues selective for the α4β2 over α7 nicotinic acetylcholine receptors",

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",

author = "Ryan Gallagher and Taima Qudah and Thomas Balle and Mary Chebib and McLeod, {Malcolm D.}",

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doi = "10.1016/j.bmc.2021.116516",

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T1 - Novel methyllycaconitine analogues selective for the α4β2 over α7 nicotinic acetylcholine receptors

AU - Gallagher, Ryan

AU - Qudah, Taima

AU - Balle, Thomas

AU - Chebib, Mary

AU - McLeod, Malcolm D.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

KW - Alpha4beta2

KW - Ligand-gated ion channel

KW - Methyllycaconitine

KW - Nicotinic acetylcholine receptor

KW - Noncompetitive antagonist

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U2 - 10.1016/j.bmc.2021.116516

DO - 10.1016/j.bmc.2021.116516

M3 - Article

SN - 0968-0896

VL - 51

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 116516

ER -

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

Abstract

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