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Publication Abstract from PubMed

alpha6beta4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions are not fully understood, largely because of a lack of specific ligands. Here, we characterized a novel alpha-conotoxin, LvIC, and designed a series of analogues to probe structure-activity relationships at the alpha6beta4 nAChR. The potency and selectivity of these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes expressed in Xenopus laevis oocytes. One of the analogues, [D1G,DeltaQ14]LvIC, potently blocked alpha6/alpha3beta4 nAChRs (alpha6/alpha3 is a chimera) with an IC(50) of 19 nM, with minimal activity at other nAChR subtypes, including the structurally similar alpha6/alpha3beta2beta3 and alpha3beta4 subtypes. Using NMR, molecular docking, and receptor mutation, structure-activity relationships of [D1G,DeltaQ14]LvIC at the alpha6/alpha3beta4 nAChR were defined. It is a potent and specific antagonist of alpha6beta4 nAChRs that could potentially serve as a novel molecular probe to explore alpha6beta4 nAChR-related neurophysiological and pharmacological functions.

Discovery, Characterization, and Engineering of LvIC, an alpha4/4-Conotoxin That Selectively Blocks Rat alpha6/alpha3beta4 Nicotinic Acetylcholine Receptors.,Zhu X, Wang S, Kaas Q, Yu J, Wu Y, Harvey PJ, Zhangsun D, Craik DJ, Luo S J Med Chem. 2023 Feb 9;66(3):2020-2031. doi: 10.1021/acs.jmedchem.2c01786. Epub , 2023 Jan 22. PMID:36682014^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.