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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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{
  "DOI": "10.1021/acschemneuro.5b00107", 
  "container_title": "ACS Chem Neurosci", 
  "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.", 
  "issued": {
    "date-parts": [
      [
        2015, 
        5, 
        8
      ]
    ]
  }, 
  "abstract": "<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>", 
  "author": [
    {
      "given": "Samuel D", 
      "family": "Banister"
    }, 
    {
      "given": "Jordyn", 
      "family": "Stuart"
    }, 
    {
      "given": "Richard C", 
      "family": "Kevin"
    }, 
    {
      "given": "Amelia", 
      "family": "Edington"
    }, 
    {
      "given": "Mitchell", 
      "family": "Longworth"
    }, 
    {
      "given": "Shane M", 
      "family": "Wilkinson"
    }, 
    {
      "given": "Corinne", 
      "family": "Beinat"
    }, 
    {
      "given": "Alexandra S", 
      "family": "Buchanan"
    }, 
    {
      "given": "David E", 
      "family": "Hibbs"
    }, 
    {
      "given": "Michelle", 
      "family": "Glass"
    }, 
    {
      "given": "Mark", 
      "family": "Connor"
    }, 
    {
      "given": "Iain S", 
      "family": "McGregor"
    }, 
    {
      "given": "Michael", 
      "family": "Kassiou"
    }
  ], 
  "page": "1445-58", 
  "volume": "6", 
  "type": "article-journal", 
  "issue": "8", 
  "id": "47750"
}
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