Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor
Identifieur interne : 001C57 ( Ncbi/Checkpoint ); précédent : 001C56; suivant : 001C58Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor
Auteurs : R B Laprairie ; A M Bagher ; M E M. Kelly ; E M Denovan-WrightSource :
- British Journal of Pharmacology [ 0007-1188 ] ; 2015.
Abstract
Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 receptors.
Internalization of CB1 receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the ST
Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ9‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (ST
Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the
Url:
DOI: 10.1111/bph.13250
PubMed: 26218440
PubMed Central: 4621983
Affiliations:
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PMC:4621983Le document en format XML
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<author><name sortKey="Laprairie, R B" sort="Laprairie, R B" uniqKey="Laprairie R" first="R B" last="Laprairie">R B Laprairie</name>
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<author><name sortKey="Bagher, A M" sort="Bagher, A M" uniqKey="Bagher A" first="A M" last="Bagher">A M Bagher</name>
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<author><name sortKey="Kelly, M E M" sort="Kelly, M E M" uniqKey="Kelly M" first="M E M" last="Kelly">M E M. Kelly</name>
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<author><name sortKey="Denovan Right, E M" sort="Denovan Right, E M" uniqKey="Denovan Right E" first="E M" last="Denovan-Wright">E M Denovan-Wright</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cannabidiol is a negative allosteric modulator of the cannabinoid CB<sub>1</sub>
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<author><name sortKey="Laprairie, R B" sort="Laprairie, R B" uniqKey="Laprairie R" first="R B" last="Laprairie">R B Laprairie</name>
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<author><name sortKey="Bagher, A M" sort="Bagher, A M" uniqKey="Bagher A" first="A M" last="Bagher">A M Bagher</name>
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<author><name sortKey="Kelly, M E M" sort="Kelly, M E M" uniqKey="Kelly M" first="M E M" last="Kelly">M E M. Kelly</name>
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<author><name sortKey="Denovan Right, E M" sort="Denovan Right, E M" uniqKey="Denovan Right E" first="E M" last="Denovan-Wright">E M Denovan-Wright</name>
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<series><title level="j">British Journal of Pharmacology</title>
<idno type="ISSN">0007-1188</idno>
<idno type="eISSN">1476-5381</idno>
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<front><div type="abstract" xml:lang="en"><sec id="bph13250-sec-0001"><title>Background and Purpose</title>
<p>Cannabidiol has been reported to act as an antagonist at cannabinoid CB<sub>1</sub>
receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB<sub>1</sub>
receptors.</p>
</sec>
<sec id="bph13250-sec-0002"><title>Experimental Approach</title>
<p>Internalization of CB<sub>1</sub>
receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB<sub>1</sub>
receptors and in the ST<italic>Hdh</italic>
<sup>Q7/Q7</sup>
cell model of striatal neurons endogenously expressing CB<sub>1</sub>
receptors. Cells were treated with 2‐arachidonylglycerol or Δ<sup>9</sup>
‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.</p>
</sec>
<sec id="bph13250-sec-0003"><title>Key Results</title>
<p>Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ<sup>9</sup>
‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (ST<italic>Hdh</italic>
<sup>Q7/Q7</sup>
) expressing CB<sub>1</sub>
receptors. By reducing arrestin2 recruitment to CB<sub>1</sub>
receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB<sub>1</sub>
receptor.</p>
</sec>
<sec id="bph13250-sec-0004"><title>Conclusions and Implications</title>
<p>Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB<sub>1</sub>
receptors. Allosteric modulation, in conjunction with effects not mediated by CB<sub>1</sub>
receptors, may explain the <italic>in vivo</italic>
effects of cannabidiol. Allosteric modulators of CB<sub>1</sub>
receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.</p>
</sec>
</div>
</front>
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<tree><noCountry><name sortKey="Bagher, A M" sort="Bagher, A M" uniqKey="Bagher A" first="A M" last="Bagher">A M Bagher</name>
<name sortKey="Denovan Right, E M" sort="Denovan Right, E M" uniqKey="Denovan Right E" first="E M" last="Denovan-Wright">E M Denovan-Wright</name>
<name sortKey="Kelly, M E M" sort="Kelly, M E M" uniqKey="Kelly M" first="M E M" last="Kelly">M E M. Kelly</name>
<name sortKey="Laprairie, R B" sort="Laprairie, R B" uniqKey="Laprairie R" first="R B" last="Laprairie">R B Laprairie</name>
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