Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

Abstract The first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) o...

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Autores principales:	Ayat Zagzoog, Asher L. Brandt, Tallan Black, Eunhyun D. Kim, Riley Burkart, Mikin Patel, Zhiyun Jin, Maria Nikolaeva, Robert B. Laprairie
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b6aa1fa4ea2b4839a0bdba526e98a3e7
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spelling	oai:doaj.org-article:b6aa1fa4ea2b4839a0bdba526e98a3e72021-12-02T15:45:20ZAssessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor10.1038/s41598-021-90167-w2045-2322https://doaj.org/article/b6aa1fa4ea2b4839a0bdba526e98a3e72021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90167-whttps://doaj.org/toc/2045-2322Abstract The first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.Ayat ZagzoogAsher L. BrandtTallan BlackEunhyun D. KimRiley BurkartMikin PatelZhiyun JinMaria NikolaevaRobert B. LaprairieNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ayat Zagzoog Asher L. Brandt Tallan Black Eunhyun D. Kim Riley Burkart Mikin Patel Zhiyun Jin Maria Nikolaeva Robert B. Laprairie Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
description	Abstract The first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.
format	article
author	Ayat Zagzoog Asher L. Brandt Tallan Black Eunhyun D. Kim Riley Burkart Mikin Patel Zhiyun Jin Maria Nikolaeva Robert B. Laprairie
author_facet	Ayat Zagzoog Asher L. Brandt Tallan Black Eunhyun D. Kim Riley Burkart Mikin Patel Zhiyun Jin Maria Nikolaeva Robert B. Laprairie
author_sort	Ayat Zagzoog
title	Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
title_short	Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
title_full	Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
title_fullStr	Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
title_full_unstemmed	Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
title_sort	assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b6aa1fa4ea2b4839a0bdba526e98a3e7
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Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

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