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: | , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/133378 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/133378 |
| Access Level: | acceso abierto |
| Palabra clave: | CBD CBDV CBDA-Derivatives (−)- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory neuroprotective effects Farmacología (Medicina) 6113 Psicofarmacología 3209 Farmacología |
| id |
ES_97cfa53eef5b116edd5c5bbbfbfa3ff3 |
|---|---|
| oai_identifier_str |
oai:docta.ucm.es:20.500.14352/133378 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
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 Cañas, MaríaLubrini, FrancescaGonzalo Consuegra, ClaudiaWinkler, MatthiasCaprioglio, DiegoAppendino, GiovanniGarcía García, María De La ConcepciónMorales, PaulaJagerovic, NadineFischer, Joerg T.Fiebich, Bernd L.Goetz, Marcus R.Muñoz, EduardoFernández Ruiz, José JavierCBDCBDVCBDA-Derivatives(−)- and (+)-enantiomersCB1 receptorCB2 receptorBindingAgonistInverse agonistAntagonistAnti-inflammatoryneuroprotective effectsFarmacología (Medicina)6113 Psicofarmacología3209 FarmacologíaCannabidiol (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, highlighting its role as a (+)-CBD target. In summary, our data show that remarkable differences between (−)- and (+)-enantiomers of CBD, CBDV and related compounds exist in terms of CB1/CB2 receptor binding profile and intrinsic activity. The observation that the natural (−)-enantiomers do not bind CB2 receptors suggests that their effects are associated with different targets.ElsevierUniversidad Complutense de Madrid20252025-08-0120252025-08-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/133378reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1333782026-06-02T12:44:21Z |
| 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 neuroprotective effects Farmacología (Medicina) 6113 Psicofarmacología 3209 Farmacología |
| 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 Cañas, María Lubrini, Francesca Gonzalo Consuegra, Claudia Winkler, Matthias Caprioglio, Diego Appendino, Giovanni García García, María De La Concepción Morales, Paula Jagerovic, Nadine Fischer, Joerg T. Fiebich, Bernd L. Goetz, Marcus R. Muñoz, Eduardo Fernández Ruiz, José Javier |
| author |
Rodríguez Carreiro, Santiago |
| author_facet |
Rodríguez Carreiro, Santiago Gómez Cañas, María Lubrini, Francesca Gonzalo Consuegra, Claudia Winkler, Matthias Caprioglio, Diego Appendino, Giovanni García García, María De La Concepción Morales, Paula Jagerovic, Nadine Fischer, Joerg T. Fiebich, Bernd L. Goetz, Marcus R. Muñoz, Eduardo Fernández Ruiz, José Javier |
| author_role |
author |
| author2 |
Gómez Cañas, María Lubrini, Francesca Gonzalo Consuegra, Claudia Winkler, Matthias Caprioglio, Diego Appendino, Giovanni García García, María De La Concepción Morales, Paula Jagerovic, Nadine Fischer, Joerg T. Fiebich, Bernd L. Goetz, Marcus R. Muñoz, Eduardo Fernández Ruiz, José Javier |
| author2_role |
author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad Complutense de Madrid |
| dc.subject.none.fl_str_mv |
CBD CBDV CBDA-Derivatives (−)- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory neuroprotective effects Farmacología (Medicina) 6113 Psicofarmacología 3209 Farmacología |
| topic |
CBD CBDV CBDA-Derivatives (−)- and (+)-enantiomers CB1 receptor CB2 receptor Binding Agonist Inverse agonist Antagonist Anti-inflammatory neuroprotective effects Farmacología (Medicina) 6113 Psicofarmacología 3209 Farmacología |
| 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, highlighting its role as a (+)-CBD target. In summary, our data show that remarkable differences between (−)- and (+)-enantiomers of CBD, CBDV and related compounds exist in terms of CB1/CB2 receptor binding profile and intrinsic activity. The observation that the natural (−)-enantiomers do not bind CB2 receptors suggests that their effects are associated with different targets. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025-08-01 2025 2025-08-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.14352/133378 |
| url |
https://hdl.handle.net/20.500.14352/133378 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
| dc.source.none.fl_str_mv |
reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM) |
| instname_str |
Universidad Complutense de Madrid (UCM) |
| reponame_str |
Docta Complutense |
| collection |
Docta Complutense |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869414109986947072 |
| score |
15,811543 |