Journal article Open Access

Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135.

Banister, Samuel D; Stuart, Jordyn; Kevin, Richard C; Edington, Amelia; Longworth, Mitchell; Wilkinson, Shane M; Beinat, Corinne; Buchanan, Alexandra S; Hibbs, David E; Glass, Michelle; Connor, Mark; McGregor, Iain S; Kassiou, Michael


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  <identifier identifierType="URL">https://zenodo.org/record/47750</identifier>
  <creators>
    <creator>
      <creatorName>Banister, Samuel D</creatorName>
      <givenName>Samuel D</givenName>
      <familyName>Banister</familyName>
    </creator>
    <creator>
      <creatorName>Stuart, Jordyn</creatorName>
      <givenName>Jordyn</givenName>
      <familyName>Stuart</familyName>
    </creator>
    <creator>
      <creatorName>Kevin, Richard C</creatorName>
      <givenName>Richard C</givenName>
      <familyName>Kevin</familyName>
    </creator>
    <creator>
      <creatorName>Edington, Amelia</creatorName>
      <givenName>Amelia</givenName>
      <familyName>Edington</familyName>
    </creator>
    <creator>
      <creatorName>Longworth, Mitchell</creatorName>
      <givenName>Mitchell</givenName>
      <familyName>Longworth</familyName>
    </creator>
    <creator>
      <creatorName>Wilkinson, Shane M</creatorName>
      <givenName>Shane M</givenName>
      <familyName>Wilkinson</familyName>
    </creator>
    <creator>
      <creatorName>Beinat, Corinne</creatorName>
      <givenName>Corinne</givenName>
      <familyName>Beinat</familyName>
    </creator>
    <creator>
      <creatorName>Buchanan, Alexandra S</creatorName>
      <givenName>Alexandra S</givenName>
      <familyName>Buchanan</familyName>
    </creator>
    <creator>
      <creatorName>Hibbs, David E</creatorName>
      <givenName>David E</givenName>
      <familyName>Hibbs</familyName>
    </creator>
    <creator>
      <creatorName>Glass, Michelle</creatorName>
      <givenName>Michelle</givenName>
      <familyName>Glass</familyName>
    </creator>
    <creator>
      <creatorName>Connor, Mark</creatorName>
      <givenName>Mark</givenName>
      <familyName>Connor</familyName>
    </creator>
    <creator>
      <creatorName>McGregor, Iain S</creatorName>
      <givenName>Iain S</givenName>
      <familyName>McGregor</familyName>
    </creator>
    <creator>
      <creatorName>Kassiou, Michael</creatorName>
      <givenName>Michael</givenName>
      <familyName>Kassiou</familyName>
    </creator>
  </creators>
  <titles>
    <title>Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135.</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2015</publicationYear>
  <subjects>
    <subject> Cannabinoid</subject>
    <subject>THC</subject>
    <subject>JWH-018</subject>
    <subject>AM-2201</subject>
    <subject>XLR-11</subject>
    <subject>PB-22</subject>
  </subjects>
  <dates>
    <date dateType="Issued">2015-05-08</date>
  </dates>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/47750</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1021/acschemneuro.5b00107</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://zenodo.org/communities/inmind</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://zenodo.org/communities/ecfunded</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="https://creativecommons.org/licenses/by/4.0/legalcode">Creative Commons Attribution 4.0 International</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&lt;p&gt;Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of &lt;em&gt;N&lt;/em&gt;-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB&lt;sub&gt;1&lt;/sub&gt;) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the &lt;em&gt;in vitro&lt;/em&gt; functional activities of SC designer drugs JWH-018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB&lt;sub&gt;1&lt;/sub&gt; and CB&lt;sub&gt;2&lt;/sub&gt; receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB&lt;sub&gt;1&lt;/sub&gt; (EC&lt;sub&gt;50&lt;/sub&gt; = 2.8&amp;ndash;1959 nM) and CB&lt;sub&gt;2&lt;/sub&gt; (EC&lt;sub&gt;50&lt;/sub&gt; = 6.5&amp;ndash;206 nM) receptors, with the fluorinated analogues generally showing increased CB&lt;sub&gt;1&lt;/sub&gt; receptor potency (&amp;sim;2&amp;ndash;5 times). Additionally, the cannabimimetic activities and relative potencies of JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135 &lt;em&gt;in vivo&lt;/em&gt; were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3&amp;ndash;10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs &lt;em&gt;in vivo&lt;/em&gt;. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 &amp;gt; 5F-PB-22 = JWH-018 &amp;gt; AM-2201 &amp;gt; APICA = STS-135 = XLR-11 &amp;gt; UR-144).&lt;/p&gt;</description>
  </descriptions>
  <fundingReferences>
    <fundingReference>
      <funderName>European Commission</funderName>
      <funderIdentifier funderIdentifierType="Crossref Funder ID">10.13039/501100000780</funderIdentifier>
      <awardNumber awardURI="info:eu-repo/grantAgreement/EC/FP7/278850/">278850</awardNumber>
      <awardTitle>Imaging of Neuroinflammation in Neurodegenerative Diseases</awardTitle>
    </fundingReference>
  </fundingReferences>
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