Cargando…

A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical signif...

Descripción completa

Detalles Bibliográficos
Autores principales: Xing, Hong, Keshwah, Sunil, Rouchaud, Anne, Kem, William R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073524/
https://www.ncbi.nlm.nih.gov/pubmed/32053997
http://dx.doi.org/10.3390/md18020106
_version_ 1783506637788545024
author Xing, Hong
Keshwah, Sunil
Rouchaud, Anne
Kem, William R.
author_facet Xing, Hong
Keshwah, Sunil
Rouchaud, Anne
Kem, William R.
author_sort Xing, Hong
collection PubMed
description Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.
format Online
Article
Text
id pubmed-7073524
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-70735242020-03-20 A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine Xing, Hong Keshwah, Sunil Rouchaud, Anne Kem, William R. Mar Drugs Article Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders. MDPI 2020-02-11 /pmc/articles/PMC7073524/ /pubmed/32053997 http://dx.doi.org/10.3390/md18020106 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xing, Hong
Keshwah, Sunil
Rouchaud, Anne
Kem, William R.
A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine
title A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine
title_full A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine
title_fullStr A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine
title_full_unstemmed A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine
title_short A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine
title_sort pharmacological comparison of two isomeric nicotinic receptor agonists: the marine toxin isoanatabine and the tobacco alkaloid anatabine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073524/
https://www.ncbi.nlm.nih.gov/pubmed/32053997
http://dx.doi.org/10.3390/md18020106
work_keys_str_mv AT xinghong apharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT keshwahsunil apharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT rouchaudanne apharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT kemwilliamr apharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT xinghong pharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT keshwahsunil pharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT rouchaudanne pharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine
AT kemwilliamr pharmacologicalcomparisonoftwoisomericnicotinicreceptoragoniststhemarinetoxinisoanatabineandthetobaccoalkaloidanatabine