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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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    <dct: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.</dct:title>
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    <dcat:keyword>Cannabinoid</dcat:keyword>
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    <dcat:keyword>JWH-018</dcat:keyword>
    <dcat:keyword>AM-2201</dcat:keyword>
    <dcat:keyword>XLR-11</dcat:keyword>
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        <foaf:name>European Commission</foaf:name>
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    <dct:description>&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;</dct:description>
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