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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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{
  "description": "<p>Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of <em>N</em>-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB<sub>1</sub>) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the <em>in vitro</em> 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<sub>1</sub> and CB<sub>2</sub> receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB<sub>1</sub> (EC<sub>50</sub> = 2.8&ndash;1959 nM) and CB<sub>2</sub> (EC<sub>50</sub> = 6.5&ndash;206 nM) receptors, with the fluorinated analogues generally showing increased CB<sub>1</sub> receptor potency (&sim;2&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 <em>in vivo</em> were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3&ndash;10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs <em>in vivo</em>. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 &gt; 5F-PB-22 = JWH-018 &gt; AM-2201 &gt; APICA = STS-135 = XLR-11 &gt; UR-144).</p>", 
  "license": "https://creativecommons.org/licenses/by/4.0/legalcode", 
  "creator": [
    {
      "@type": "Person", 
      "name": "Banister, Samuel D"
    }, 
    {
      "@type": "Person", 
      "name": "Stuart, Jordyn"
    }, 
    {
      "@type": "Person", 
      "name": "Kevin, Richard C"
    }, 
    {
      "@type": "Person", 
      "name": "Edington, Amelia"
    }, 
    {
      "@type": "Person", 
      "name": "Longworth, Mitchell"
    }, 
    {
      "@type": "Person", 
      "name": "Wilkinson, Shane M"
    }, 
    {
      "@type": "Person", 
      "name": "Beinat, Corinne"
    }, 
    {
      "@type": "Person", 
      "name": "Buchanan, Alexandra S"
    }, 
    {
      "@type": "Person", 
      "name": "Hibbs, David E"
    }, 
    {
      "@type": "Person", 
      "name": "Glass, Michelle"
    }, 
    {
      "@type": "Person", 
      "name": "Connor, Mark"
    }, 
    {
      "@type": "Person", 
      "name": "McGregor, Iain S"
    }, 
    {
      "@type": "Person", 
      "name": "Kassiou, Michael"
    }
  ], 
  "headline": "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.", 
  "image": "https://zenodo.org/static/img/logos/zenodo-gradient-round.svg", 
  "datePublished": "2015-05-08", 
  "url": "https://zenodo.org/record/47750", 
  "keywords": [
    " Cannabinoid", 
    "THC", 
    "JWH-018", 
    "AM-2201", 
    "XLR-11", 
    "PB-22"
  ], 
  "@context": "https://schema.org/", 
  "identifier": "https://doi.org/10.1021/acschemneuro.5b00107", 
  "@id": "https://doi.org/10.1021/acschemneuro.5b00107", 
  "@type": "ScholarlyArticle", 
  "name": "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."
}
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