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Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor

Identifieur interne : 000345 ( Pmc/Checkpoint ); précédent : 000344; suivant : 000346

Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor

Auteurs : R B Laprairie ; A M Bagher ; M E M. Kelly ; E M Denovan-Wright

Source :

British Journal of Pharmacology [ 0007-1188 ] ; 2015.

RBID : PMC:4621983

Abstract

Background and Purpose

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.

Experimental Approach

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 STHdh^Q7/Q7 cell model of striatal neurons endogenously expressing CB₁ receptors. Cells were treated with 2‐arachidonylglycerol or Δ⁹‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.

Key Results

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 (STHdh^Q7/Q7) expressing CB₁ receptors. By reducing arrestin2 recruitment to CB₁ 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 CB₁ receptor.

Conclusions and Implications

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 in vivo effects of cannabidiol. Allosteric modulators of CB₁ receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621983

DOI: 10.1111/bph.13250
PubMed: 26218440
PubMed Central: 4621983

Affiliations:

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<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>
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<alt-title alt-title-type="right-running-head">Negative allosteric modulation of CB<sub>1</sub>
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<alt-title alt-title-type="left-running-head">R B Laprairie et al.</alt-title>
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<contrib id="bph13250-cr-0003" contrib-type="author"><name><surname>Kelly</surname>
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<xref ref-type="aff" rid="bph13250-aff-0001"><sup>1</sup>
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<xref ref-type="aff" rid="bph13250-aff-0002"><sup>2</sup>
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<contrib id="bph13250-cr-0004" contrib-type="author" corresp="yes"><name><surname>Denovan‐Wright</surname>
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<xref ref-type="aff" rid="bph13250-aff-0001"><sup>1</sup>
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<aff id="bph13250-aff-0001"><label><sup>1</sup>
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<named-content content-type="organisation-division">Departments of Pharmacology</named-content>
<institution>Dalhousie University</institution>
<named-content content-type="city">Halifax</named-content>
<named-content content-type="country-part">NS</named-content>
<country country="CA">Canada</country>
</aff>
<aff id="bph13250-aff-0002"><label><sup>2</sup>
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<named-content content-type="organisation-division">Opthamology and Visual Sciences</named-content>
<institution>Dalhousie University</institution>
<named-content content-type="city">Halifax</named-content>
<named-content content-type="country-part">NS</named-content>
<country country="CA">Canada</country>
</aff>
<author-notes><corresp id="correspondenceTo"><label>*</label>
Correspondence<break></break>
Eileen M Denovan‐Wright, PhD, Department of Pharmacology, Dalhousie University, Rm 6E 5850 College St, Halifax, NS, B3H 4R2, Canada. E‐mail: <email>emdenova@dal.ca</email>
<break></break>
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<pub-date pub-type="epub"><day>13</day>
<month>10</month>
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<pub-date pub-type="ppub"><month>10</month>
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<history><date date-type="received"><day>13</day>
<month>2</month>
<year>2015</year>
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<date date-type="rev-recd"><day>04</day>
<month>6</month>
<year>2015</year>
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<date date-type="accepted"><day>08</day>
<month>7</month>
<year>2015</year>
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<permissions><pmc-comment> Copyright © 2015 The British Pharmacological Society </pmc-comment>
        <copyright-statement content-type="article-copyright">© 2015 The British Pharmacological Society</copyright-statement>
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<abstract abstract-type="main"><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>
</abstract>
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<notes><p content-type="self-citation"><mixed-citation publication-type="journal" id="bph13250-cit-0000"><string-name><surname>Laprairie</surname>
, <given-names>R. B.</given-names>
</string-name>
, <string-name><surname>Bagher</surname>
, <given-names>A. M.</given-names>
</string-name>
, <string-name><surname>Kelly</surname>
, <given-names>M. E. M.</given-names>
</string-name>
, and <string-name><surname>Denovan‐Wright</surname>
, <given-names>E. M.</given-names>
</string-name>
 (<year>2015</year>
) <article-title>Cannabidiol is a negative allosteric modulator of the cannabinoid CB<sub>1</sub>
 receptor</article-title>
. <source>British Journal of Pharmacology</source>
, <volume>172</volume>
: <fpage>4790</fpage>
–<lpage>4805</lpage>
. doi: <ext-link ext-link-type="doi" xlink:href="10.1111/bph.13250">10.1111/bph.13250</ext-link>
.<pub-id pub-id-type="pmid">26218440</pub-id>
</mixed-citation>
</p>
</notes>
</front>
</pmc>
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<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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Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor

Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor

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Abstract

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