Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Pharmacologically distinguishing α3β2 nicotinic acetylcholine receptors (nAChRs) from closely related subtypes, particularly α6β2, has been challenging due to the lack of subtype-selective ligands. We created analogs of α-conotoxin (α-Ctx) PeIA to identify ligand-receptor interactions that could be exploited to selectively increase potency and selectivity for α3β2 nAChRs. A series of PeIA analogs were synthesized by replacing amino acid residues in the second disulfide loop with standard or nonstandard residues and assessing their activity on α3β2 and α6/α3β2β3 nAChRs heterologously expressed in Xenopus laevis oocytes. Asparagine11 was found to occupy a pivotal position, and when replaced with negatively charged amino acids, selectivity for α3β2 over α6/α3β2β3 nAChRs was substantially increased. Second generation peptides were then designed to further improve both potency and selectivity. One peptide, PeIA-5466, was ∼300-fold more potent on α3β2 than α6/α3β2β3 and is the most α3β2-selective antagonist heretofore reported.
???displayArticle.pubmedLink???
31194549 ???displayArticle.pmcLink???PMC7342494 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Alexander,
The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels.
2015, Pubmed
Alexander,
The Concise Guide to PHARMACOLOGY 2015/16: Ligand-gated ion channels.
2015,
Pubmed Azam,
Amino acid residues that confer high selectivity of the alpha6 nicotinic acetylcholine receptor subunit to alpha-conotoxin MII[S4A,E11A,L15A].
2008,
Pubmed
,
Xenbase Azam,
α-Conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between α6ß4 and α6ß2 nicotinic acetylcholine receptors and blocks nicotine-stimulated norepinephrine release.
2010,
Pubmed
,
Xenbase Baddick,
An autoradiographic survey of mouse brain nicotinic acetylcholine receptors defined by null mutants.
2011,
Pubmed Brunzell,
Preclinical evidence that activation of mesolimbic alpha 6 subunit containing nicotinic acetylcholine receptors supports nicotine addiction phenotype.
2012,
Pubmed Bürgi,
Discovery of potent positive allosteric modulators of the α3β2 nicotinic acetylcholine receptor by a chemical space walk in ChEMBL.
2014,
Pubmed
,
Xenbase Champtiaux,
Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice.
2002,
Pubmed Chi,
Solution conformation of a neuronal nicotinic acetylcholine receptor antagonist alpha-conotoxin OmIA that discriminates alpha3 vs. alpha6 nAChR subtypes.
2006,
Pubmed David,
Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes.
2010,
Pubmed
,
Xenbase Dutertre,
Nicotinic acetylcholine receptor inhibitors derived from snake and snail venoms.
2017,
Pubmed Giribaldi,
α-Conotoxins to explore the molecular, physiological and pathophysiological functions of neuronal nicotinic acetylcholine receptors.
2018,
Pubmed Gotti,
Expression of nigrostriatal alpha 6-containing nicotinic acetylcholine receptors is selectively reduced, but not eliminated, by beta 3 subunit gene deletion.
2005,
Pubmed Gotti,
Brain nicotinic acetylcholine receptors: native subtypes and their relevance.
2006,
Pubmed Grady,
Characterization of nicotinic agonist-induced [(3)H]dopamine release from synaptosomes prepared from four mouse brain regions.
2002,
Pubmed Hone,
α-Conotoxins Identify the α3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells.
2015,
Pubmed
,
Xenbase Hone,
Nicotinic acetylcholine receptors in neuropathic and inflammatory pain.
2018,
Pubmed Hone,
Positional scanning mutagenesis of α-conotoxin PeIA identifies critical residues that confer potency and selectivity for α6/α3β2β3 and α3β2 nicotinic acetylcholine receptors.
2013,
Pubmed
,
Xenbase Hone,
Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors.
2018,
Pubmed
,
Xenbase Hone,
α-Conotoxin PeIA[S9H,V10A,E14N] potently and selectively blocks α6β2β3 versus α6β4 nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase Innocent,
Alpha-conotoxin Arenatus IB[V11L,V16D] [corrected] is a potent and selective antagonist at rat and human native alpha7 nicotinic acetylcholine receptors.
2008,
Pubmed
,
Xenbase Kulak,
Alpha-conotoxin MII blocks nicotine-stimulated dopamine release in rat striatal synaptosomes.
1997,
Pubmed Kuryatov,
Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses.
2000,
Pubmed
,
Xenbase Luo,
A novel α4/7-conotoxin LvIA from Conus lividus that selectively blocks α3β2 vs. α6/α3β2β3 nicotinic acetylcholine receptors.
2014,
Pubmed
,
Xenbase Mao,
Heterogeneity of nicotinic cholinergic receptors in rat superior cervical and nodose Ganglia.
2006,
Pubmed Marritt,
Nicotinic cholinergic receptors in the rat retina: simple and mixed heteromeric subtypes.
2005,
Pubmed McIntosh,
Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors.
2004,
Pubmed
,
Xenbase McIntosh,
A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors.
2005,
Pubmed
,
Xenbase Prashanth,
Pharmacology of predatory and defensive venom peptides in cone snails.
2017,
Pubmed Pucci,
Engineering of α-conotoxin MII-derived peptides with increased selectivity for native α6β2* nicotinic acetylcholine receptors.
2011,
Pubmed Quik,
Subunit composition of nicotinic receptors in monkey striatum: effect of treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or L-DOPA.
2005,
Pubmed Romero,
Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain.
2017,
Pubmed Salminen,
The subunit composition and pharmacology of alpha-Conotoxin MII-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay.
2005,
Pubmed Simeone,
The role of the nAChR subunits α5, β2, and β4 on synaptic transmission in the mouse superior cervical ganglion.
2019,
Pubmed Talley,
Alpha-conotoxin OmIA is a potent ligand for the acetylcholine-binding protein as well as alpha3beta2 and alpha7 nicotinic acetylcholine receptors.
2006,
Pubmed
,
Xenbase Tsetlin,
Polypeptide and peptide toxins, magnifying lenses for binding sites in nicotinic acetylcholine receptors.
2009,
Pubmed Turner,
Mutagenesis of α-Conotoxins for Enhancing Activity and Selectivity for Nicotinic Acetylcholine Receptors.
2019,
Pubmed Whiteaker,
Involvement of the alpha3 subunit in central nicotinic binding populations.
2002,
Pubmed Whiteaker,
Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist.
2007,
Pubmed
,
Xenbase Wu,
α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors.
2017,
Pubmed
,
Xenbase Yu,
Single Amino Acid Substitution in α-Conotoxin TxID Reveals a Specific α3β4 Nicotinic Acetylcholine Receptor Antagonist.
2018,
Pubmed Zoli,
Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum.
2002,
Pubmed
