Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, have been developed to investigate the DOR in vivo and as potential therapeutics for pain and dep...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Parthasaradhireddy Tanguturi, Vibha Pathak, Sixue Zhang, Omar Moukha-Chafiq, Corinne E. Augelli-Szafran, John M. Streicher
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	delta opioid receptor inverse agonist irreversible antagonist non-competitive antagonist molecular pharmacology Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/b9531487f7ba4d92a97a741674b91326
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b9531487f7ba4d92a97a741674b91326
record_format	dspace
spelling	oai:doaj.org-article:b9531487f7ba4d92a97a741674b913262021-11-11T18:38:38ZDiscovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists10.3390/molecules262166931420-3049https://doaj.org/article/b9531487f7ba4d92a97a741674b913262021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6693https://doaj.org/toc/1420-3049The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, have been developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45127/SRI-45128 as inverse agonists. Then, these compounds were evaluated in vitro for their binding affinity by radioligand binding and functional activity by <sup>35</sup>S-GTPγS coupling and cAMP accumulation in cells expressing the human DOR. All three compounds demonstrated high binding affinity and selectivity at the DOR, and all three displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45127/SRI-45128). Together, these results demonstrate that we have designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.Parthasaradhireddy TanguturiVibha PathakSixue ZhangOmar Moukha-ChafiqCorinne E. Augelli-SzafranJohn M. StreicherMDPI AGarticledelta opioid receptorinverse agonistirreversible antagonistnon-competitive antagonistmolecular pharmacologyOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6693, p 6693 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	delta opioid receptor inverse agonist irreversible antagonist non-competitive antagonist molecular pharmacology Organic chemistry QD241-441
spellingShingle	delta opioid receptor inverse agonist irreversible antagonist non-competitive antagonist molecular pharmacology Organic chemistry QD241-441 Parthasaradhireddy Tanguturi Vibha Pathak Sixue Zhang Omar Moukha-Chafiq Corinne E. Augelli-Szafran John M. Streicher Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists
description	The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, have been developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45127/SRI-45128 as inverse agonists. Then, these compounds were evaluated in vitro for their binding affinity by radioligand binding and functional activity by <sup>35</sup>S-GTPγS coupling and cAMP accumulation in cells expressing the human DOR. All three compounds demonstrated high binding affinity and selectivity at the DOR, and all three displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45127/SRI-45128). Together, these results demonstrate that we have designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.
format	article
author	Parthasaradhireddy Tanguturi Vibha Pathak Sixue Zhang Omar Moukha-Chafiq Corinne E. Augelli-Szafran John M. Streicher
author_facet	Parthasaradhireddy Tanguturi Vibha Pathak Sixue Zhang Omar Moukha-Chafiq Corinne E. Augelli-Szafran John M. Streicher
author_sort	Parthasaradhireddy Tanguturi
title	Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists
title_short	Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists
title_full	Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists
title_fullStr	Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists
title_full_unstemmed	Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists
title_sort	discovery of novel delta opioid receptor (dor) inverse agonist and irreversible (non-competitive) antagonists
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b9531487f7ba4d92a97a741674b91326
work_keys_str_mv	AT parthasaradhireddytanguturi discoveryofnoveldeltaopioidreceptordorinverseagonistandirreversiblenoncompetitiveantagonists AT vibhapathak discoveryofnoveldeltaopioidreceptordorinverseagonistandirreversiblenoncompetitiveantagonists AT sixuezhang discoveryofnoveldeltaopioidreceptordorinverseagonistandirreversiblenoncompetitiveantagonists AT omarmoukhachafiq discoveryofnoveldeltaopioidreceptordorinverseagonistandirreversiblenoncompetitiveantagonists AT corinneeaugelliszafran discoveryofnoveldeltaopioidreceptordorinverseagonistandirreversiblenoncompetitiveantagonists AT johnmstreicher discoveryofnoveldeltaopioidreceptordorinverseagonistandirreversiblenoncompetitiveantagonists
_version_	1718431783449526272

Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

Ejemplares similares