Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives
Cannabidiol (CBD) and cannabidivarin (CBDV) have shown promising clinical efficacy for the management of epilepsy, and beneficial effects have been demonstrated for CBD in a diversity of other pathologies (pain, schizophrenia, Tourette syndrome, anxiety). However, the mechanism(s) involved are still...
| Autores: | , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/388571 |
| Acceso en línea: | http://hdl.handle.net/10261/388571 |
| Access Level: | acceso abierto |
| Palabra clave: | CBD CBDV CBDA-Derivatives ( )- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory and neuroprotective effects |
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Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivativesRodríguez-Carreiro, SantiagoGómez-Cañasa, MaríaLubrinia, FrancescaGonzalo-Consuegra, ClaudiaWinklerd, MatthiasCaprioglio, DiegoAppendino, GiovanniGarcía, ConcepciónMorales, PaulaJagerovic, NadineFischer, Joerg T.Fiebich, Bernd L.Goetz, Marcus R.Muñoz, EduardoFernández-Ruiz, JavierCBDCBDVCBDA-Derivatives( )- and (+)-enantiomersCB1 receptorCB2 receptorBindingAgonistInverse agonistAntagonistAnti-inflammatory and neuroprotective effectsCannabidiol (CBD) and cannabidivarin (CBDV) have shown promising clinical efficacy for the management of epilepsy, and beneficial effects have been demonstrated for CBD in a diversity of other pathologies (pain, schizophrenia, Tourette syndrome, anxiety). However, the mechanism(s) involved are still largely elusive, as are the molecular target(s) involved. CBD and CBDV do not orthosterically bind the cannabinoid type-1 (CB1) and type-2 (CB2) receptors, showing only modest allosteric modulation of both end-points. CBD and CBDV are biosynthesized as optically highly pure ( )-enantiomers, and most bioactivity data refer to these forms. (+)-CBD and related analogues [(+)-cannabidiolic acid (CBDA), its esters, and (+)-CBDV] can be obtained by chemical synthesis, and we present evidence that the (+)- and ( )-enantiomers of CBD, CBDV and of a selection of derivatives of CBDA have distinct binding profiles and functional activity at the CB1/CB2 receptors. Thus, with the single exception of the methyl ester of CBDA, all the (+)-enantiomers showed higher affinities than the ( )-isomers for both receptors, in particular for the CB2 receptors. The affinity of the (+)-enantiomers for both CB1 and CB2 receptors showed a marked dependence on the nature of the alkyl residue on the aromatic ring and the esterification pattern of CBDA. Potency was rarely in the low nM value for CB1, but generally so for CB2. Enantiomers showing low nM activity were further investigated for their intrinsic activity using GTPγS binding assays. This proved that (+)-CBD, (+)-CBDV and the methyl ester of (+)-CBDA are agonists at the CB2 receptor, with the β-hydroxyethyl ester of (+)-CBDA being an inverse agonist, and its β-hydroxypentyl ester behaving as an agonist at CB1 and an inverse agonist at CB2. Finally, we assayed in vitro the anti-inflammatory and neuroprotective properties of three compounds [(+)-CBD, (+)-CBDV and (+)-CBDA methyl ester] strongly activating CB2, showing their ability to reduce the production of proinflammatory factors and protecting neurons against their toxicity. Remarkably, these benefits were eliminated by the selective blockade of the CB2 receptor,Authors want to thank the support by grants from MCINN “Programa Nacional de Biomedicina” (PID2021-128906OB-I00 to JF-R) with co- funding from the European Regional Development Funds (FEDER), “Instituto de Salud Carlos III” (CIBERNED, CB06/05/0089), Symrise AG, Holzminden, Germany, and VivaCell Biotechnology-Spain. These agencies had no further role in study design, the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.Peer reviewedElsevierMinisterio de Ciencia e Innovación (España)European CommissionInstituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/388571reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#PID2021-128906OB-I00https://doi.org/10.1016/j.ejmcr.2025.100262Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3885712026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| title |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| spellingShingle |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives Rodríguez-Carreiro, Santiago CBD CBDV CBDA-Derivatives ( )- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory and neuroprotective effects |
| title_short |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| title_full |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| title_fullStr |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| title_full_unstemmed |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| title_sort |
Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of ( ) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives |
| dc.creator.none.fl_str_mv |
Rodríguez-Carreiro, Santiago Gómez-Cañasa, María Lubrinia, Francesca Gonzalo-Consuegra, Claudia Winklerd, Matthias Caprioglio, Diego Appendino, Giovanni García, Concepción Morales, Paula Jagerovic, Nadine Fischer, Joerg T. Fiebich, Bernd L. Goetz, Marcus R. Muñoz, Eduardo Fernández-Ruiz, Javier |
| author |
Rodríguez-Carreiro, Santiago |
| author_facet |
Rodríguez-Carreiro, Santiago Gómez-Cañasa, María Lubrinia, Francesca Gonzalo-Consuegra, Claudia Winklerd, Matthias Caprioglio, Diego Appendino, Giovanni García, Concepción Morales, Paula Jagerovic, Nadine Fischer, Joerg T. Fiebich, Bernd L. Goetz, Marcus R. Muñoz, Eduardo Fernández-Ruiz, Javier |
| author_role |
author |
| author2 |
Gómez-Cañasa, María Lubrinia, Francesca Gonzalo-Consuegra, Claudia Winklerd, Matthias Caprioglio, Diego Appendino, Giovanni García, Concepción Morales, Paula Jagerovic, Nadine Fischer, Joerg T. Fiebich, Bernd L. Goetz, Marcus R. Muñoz, Eduardo Fernández-Ruiz, Javier |
| author2_role |
author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Ciencia e Innovación (España) European Commission Instituto de Salud Carlos III Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
CBD CBDV CBDA-Derivatives ( )- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory and neuroprotective effects |
| topic |
CBD CBDV CBDA-Derivatives ( )- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory and neuroprotective effects |
| description |
Cannabidiol (CBD) and cannabidivarin (CBDV) have shown promising clinical efficacy for the management of epilepsy, and beneficial effects have been demonstrated for CBD in a diversity of other pathologies (pain, schizophrenia, Tourette syndrome, anxiety). However, the mechanism(s) involved are still largely elusive, as are the molecular target(s) involved. CBD and CBDV do not orthosterically bind the cannabinoid type-1 (CB1) and type-2 (CB2) receptors, showing only modest allosteric modulation of both end-points. CBD and CBDV are biosynthesized as optically highly pure ( )-enantiomers, and most bioactivity data refer to these forms. (+)-CBD and related analogues [(+)-cannabidiolic acid (CBDA), its esters, and (+)-CBDV] can be obtained by chemical synthesis, and we present evidence that the (+)- and ( )-enantiomers of CBD, CBDV and of a selection of derivatives of CBDA have distinct binding profiles and functional activity at the CB1/CB2 receptors. Thus, with the single exception of the methyl ester of CBDA, all the (+)-enantiomers showed higher affinities than the ( )-isomers for both receptors, in particular for the CB2 receptors. The affinity of the (+)-enantiomers for both CB1 and CB2 receptors showed a marked dependence on the nature of the alkyl residue on the aromatic ring and the esterification pattern of CBDA. Potency was rarely in the low nM value for CB1, but generally so for CB2. Enantiomers showing low nM activity were further investigated for their intrinsic activity using GTPγS binding assays. This proved that (+)-CBD, (+)-CBDV and the methyl ester of (+)-CBDA are agonists at the CB2 receptor, with the β-hydroxyethyl ester of (+)-CBDA being an inverse agonist, and its β-hydroxypentyl ester behaving as an agonist at CB1 and an inverse agonist at CB2. Finally, we assayed in vitro the anti-inflammatory and neuroprotective properties of three compounds [(+)-CBD, (+)-CBDV and (+)-CBDA methyl ester] strongly activating CB2, showing their ability to reduce the production of proinflammatory factors and protecting neurons against their toxicity. Remarkably, these benefits were eliminated by the selective blockade of the CB2 receptor, |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025 2025 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/388571 |
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http://hdl.handle.net/10261/388571 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# PID2021-128906OB-I00 https://doi.org/10.1016/j.ejmcr.2025.100262 Sí |
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Elsevier |
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Elsevier |
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