Differential Enantiomer-Specific Signaling of Cannabidiol at CB 1 Receptors
The two main constituents of are Δ -tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ -THC pharmacology has been studied extensively, CBD-long considered inactive-is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-a...
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Published in | Molecular pharmacology Vol. 102; no. 6; pp. 259 - 268 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.12.2022
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Subjects | |
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Abstract | The two main constituents of
are Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ
-THC pharmacology has been studied extensively, CBD-long considered inactive-is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-all. However, our understanding of CBD pharmacology remains limited, although CBD inhibits cannabinoid CB
receptor signaling, likely as a negative allosteric modulator.
synthesizes (-)-CBD, but CBD can also exist as an enantiomer, (+)-CBD. We enantioselectively synthesized both CBD enantiomers using established conditions and describe here a new, practical, and reliable, NMR-based method for confirming the enantiomeric purity of two CBD enantiomers. We also investigated the pharmacology of (+)-CBD in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and in CHO-K1 cells. We report the inhibition constant for displacing CP55,940 at CB
by (+)-CBD, is 5-fold lower than (-)-CBD. We find that (+)-CBD is ∼10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endogenous cannabinoid-mediated retrograde synaptic plasticity. (+)-CBD also inhibits CB
suppression of cAMP accumulation but with less potency, indicating that the signaling profiles of the enantiomers differ in a pathway-specific manner. In addition, we report that (+)-CBD stereoselectively and potently activates the sphingosine-1 phosphate (S1P) receptors, S1P
and S1P
These results provide an attractive method for synthesizing and distinguishing enantiomers of CBD and related phytocannabinoids and provide further evidence that these enantiomers have their own unique and interesting signaling properties. SIGNIFICANCE STATEMENT: Cannabidiol (CBD) is the subject of considerable scientific and popular interest, but we know little of the enantiomers of CBD. We find that the enantiomer (+)-CBD is substantially more potent inhibitor of cannabinoid CB
receptors and that it activates sphingosine-1-phosphate receptors in an enantiomer-specific manner; we have additionally developed an improved method for the synthesis of enantiomers of CBD and related compounds. |
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AbstractList | The two main constituents of
are Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ
-THC pharmacology has been studied extensively, CBD-long considered inactive-is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-all. However, our understanding of CBD pharmacology remains limited, although CBD inhibits cannabinoid CB
receptor signaling, likely as a negative allosteric modulator.
synthesizes (-)-CBD, but CBD can also exist as an enantiomer, (+)-CBD. We enantioselectively synthesized both CBD enantiomers using established conditions and describe here a new, practical, and reliable, NMR-based method for confirming the enantiomeric purity of two CBD enantiomers. We also investigated the pharmacology of (+)-CBD in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and in CHO-K1 cells. We report the inhibition constant for displacing CP55,940 at CB
by (+)-CBD, is 5-fold lower than (-)-CBD. We find that (+)-CBD is ∼10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endogenous cannabinoid-mediated retrograde synaptic plasticity. (+)-CBD also inhibits CB
suppression of cAMP accumulation but with less potency, indicating that the signaling profiles of the enantiomers differ in a pathway-specific manner. In addition, we report that (+)-CBD stereoselectively and potently activates the sphingosine-1 phosphate (S1P) receptors, S1P
and S1P
These results provide an attractive method for synthesizing and distinguishing enantiomers of CBD and related phytocannabinoids and provide further evidence that these enantiomers have their own unique and interesting signaling properties. SIGNIFICANCE STATEMENT: Cannabidiol (CBD) is the subject of considerable scientific and popular interest, but we know little of the enantiomers of CBD. We find that the enantiomer (+)-CBD is substantially more potent inhibitor of cannabinoid CB
receptors and that it activates sphingosine-1-phosphate receptors in an enantiomer-specific manner; we have additionally developed an improved method for the synthesis of enantiomers of CBD and related compounds. |
Author | Wilson, Sierra Iliopoulos-Tsoutsouvas, Christos Wager-Miller, Jim Mackie, Ken P Straiker, Alex Jiang, Shan Makriyannis, Alexandros Bosquez-Berger, Taryn Nikas, Spyros P |
Author_xml | – sequence: 1 givenname: Taryn orcidid: 0000-0002-0855-9672 surname: Bosquez-Berger fullname: Bosquez-Berger, Taryn organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 2 givenname: Sierra surname: Wilson fullname: Wilson, Sierra organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 3 givenname: Christos surname: Iliopoulos-Tsoutsouvas fullname: Iliopoulos-Tsoutsouvas, Christos organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 4 givenname: Shan surname: Jiang fullname: Jiang, Shan organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 5 givenname: Jim surname: Wager-Miller fullname: Wager-Miller, Jim organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 6 givenname: Spyros P surname: Nikas fullname: Nikas, Spyros P organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 7 givenname: Ken P surname: Mackie fullname: Mackie, Ken P organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts – sequence: 8 givenname: Alexandros surname: Makriyannis fullname: Makriyannis, Alexandros email: straiker@indiana.edu, a.makriyannis@northeastern.edu organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts straiker@indiana.edu a.makriyannis@northeastern.edu – sequence: 9 givenname: Alex surname: Straiker fullname: Straiker, Alex email: straiker@indiana.edu, a.makriyannis@northeastern.edu organization: Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, Indiana (T.B., S.W., J.W.M., K.M., A.S.); and Center for Drug Discovery and Department of Pharmaceutical Sciences (C.I.T., S.P.N., A.M.) and Center for Drug Discovery and Department of Chemistry and Chemical Biology (S.J., A.M.), Northeastern University, Boston, Massachusetts straiker@indiana.edu a.makriyannis@northeastern.edu |
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Probing the cannabinoid receptor subsite at C1′ publication-title: J Med Chem doi: 10.1021/jm020558c contributor: fullname: Papahatjis |
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Snippet | The two main constituents of
are Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ
-THC pharmacology has been studied extensively, CBD-long... |
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StartPage | 259 |
SubjectTerms | Cannabidiol - pharmacology Cannabinoid Receptor Agonists - pharmacology Dronabinol - pharmacology Endocannabinoids Receptor, Cannabinoid, CB1 Receptor, Cannabinoid, CB2 Signal Transduction |
Title | Differential Enantiomer-Specific Signaling of Cannabidiol at CB 1 Receptors |
URI | https://www.ncbi.nlm.nih.gov/pubmed/36153039 |
Volume | 102 |
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