1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists

The cannabinoid receptor 2 (CB2 receptor) has attracted considerable interest, mainly due to its potential as a target for therapeutics for treating various diseases that have a neuroinflammatory or neurodegenerative component while avoiding the adverse psychotropic effects that accompany CB1 recept...

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Autores principales:	Amer H. Tarawneh, Pankaj Pandey, Lo'ay A. Al-Momani, Anastassiya V. Gadetskaya, Sultan T. Abu-Orabi, Robert J. Doerksen, Stephen J. Cutler
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Cannabinoid receptors Docking Triazole Radioligand binding assay Receptor binding Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/e155f8c981fa43f99cbbbced5bbfc653
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spelling	oai:doaj.org-article:e155f8c981fa43f99cbbbced5bbfc6532021-11-24T04:27:40Z1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists1878-535210.1016/j.arabjc.2021.103545https://doaj.org/article/e155f8c981fa43f99cbbbced5bbfc6532022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1878535221005608https://doaj.org/toc/1878-5352The cannabinoid receptor 2 (CB2 receptor) has attracted considerable interest, mainly due to its potential as a target for therapeutics for treating various diseases that have a neuroinflammatory or neurodegenerative component while avoiding the adverse psychotropic effects that accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this research, we are interested in the discovery of new chemotypes as highly selective CB2 modulators, which may serve as good starting points for further optimization towards the development of CB2 therapeutics. In search of new chemotypes as CB2 selective agents, we screened a series of triazole derivatives with interesting bioactive scaffolds, which led to the discovery of two novel and highly selective ligands for CB2 receptors. Compounds 6 and 11 produced a concentration-dependent inhibition of specific [3H]-CP55,940 (CB2) binding with Ki ± SEM values of 105.3 ± 22.6 and 116.4 ± 19.5 nM, respectively, while no binding affinity towards CB1 receptors or opioid receptors was observed. The CB2 functional activity of 6 and 11, as measured by a GPCR Tango assay (G-protein independent β-arrestin translocation assay), revealed that these compounds act as CB2 agonists with EC50 values ± SEM of 1.83 ± 0.16 and 1.14 ± 0.52 µM, respectively. Molecular modeling results showed that both compounds fit well into the active site of the CB2 receptor and showed strong hydrophobic interactions with key residues. In conclusion, the new triazole derivatives (6 and 11) showed promising activity towards CB2 receptors and have great potential to be developed into therapeutically useful CB2 agonists through hit-to-lead optimization.Amer H. TarawnehPankaj PandeyLo'ay A. Al-MomaniAnastassiya V. GadetskayaSultan T. Abu-OrabiRobert J. DoerksenStephen J. CutlerElsevierarticleCannabinoid receptorsDockingTriazoleRadioligand binding assayReceptor bindingChemistryQD1-999ENArabian Journal of Chemistry, Vol 15, Iss 1, Pp 103545- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cannabinoid receptors Docking Triazole Radioligand binding assay Receptor binding Chemistry QD1-999
spellingShingle	Cannabinoid receptors Docking Triazole Radioligand binding assay Receptor binding Chemistry QD1-999 Amer H. Tarawneh Pankaj Pandey Lo'ay A. Al-Momani Anastassiya V. Gadetskaya Sultan T. Abu-Orabi Robert J. Doerksen Stephen J. Cutler 1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists
description	The cannabinoid receptor 2 (CB2 receptor) has attracted considerable interest, mainly due to its potential as a target for therapeutics for treating various diseases that have a neuroinflammatory or neurodegenerative component while avoiding the adverse psychotropic effects that accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this research, we are interested in the discovery of new chemotypes as highly selective CB2 modulators, which may serve as good starting points for further optimization towards the development of CB2 therapeutics. In search of new chemotypes as CB2 selective agents, we screened a series of triazole derivatives with interesting bioactive scaffolds, which led to the discovery of two novel and highly selective ligands for CB2 receptors. Compounds 6 and 11 produced a concentration-dependent inhibition of specific [3H]-CP55,940 (CB2) binding with Ki ± SEM values of 105.3 ± 22.6 and 116.4 ± 19.5 nM, respectively, while no binding affinity towards CB1 receptors or opioid receptors was observed. The CB2 functional activity of 6 and 11, as measured by a GPCR Tango assay (G-protein independent β-arrestin translocation assay), revealed that these compounds act as CB2 agonists with EC50 values ± SEM of 1.83 ± 0.16 and 1.14 ± 0.52 µM, respectively. Molecular modeling results showed that both compounds fit well into the active site of the CB2 receptor and showed strong hydrophobic interactions with key residues. In conclusion, the new triazole derivatives (6 and 11) showed promising activity towards CB2 receptors and have great potential to be developed into therapeutically useful CB2 agonists through hit-to-lead optimization.
format	article
author	Amer H. Tarawneh Pankaj Pandey Lo'ay A. Al-Momani Anastassiya V. Gadetskaya Sultan T. Abu-Orabi Robert J. Doerksen Stephen J. Cutler
author_facet	Amer H. Tarawneh Pankaj Pandey Lo'ay A. Al-Momani Anastassiya V. Gadetskaya Sultan T. Abu-Orabi Robert J. Doerksen Stephen J. Cutler
author_sort	Amer H. Tarawneh
title	1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists
title_short	1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists
title_full	1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists
title_fullStr	1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists
title_full_unstemmed	1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists
title_sort	1,2,3-triazole derivatives as highly selective cannabinoid receptor type 2 (cb2) agonists
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/e155f8c981fa43f99cbbbced5bbfc653
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1,2,3-Triazole derivatives as highly selective cannabinoid receptor type 2 (CB2) agonists

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