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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.

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          Abstract

          Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro 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 CB1 and CB2 receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 2.8-1959 nM) and CB2 (EC50 = 6.5-206 nM) receptors, with the fluorinated analogues generally showing increased CB1 receptor potency (∼2-5 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 in vivo were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3-10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs in vivo. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 > 5F-PB-22 = JWH-018 > AM-2201 > APICA = STS-135 = XLR-11 > UR-144).

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          Author and article information

          Journal
          ACS Chem Neurosci
          ACS chemical neuroscience
          1948-7193
          1948-7193
          Aug 19 2015
          : 6
          : 8
          Affiliations
          [1 ] †Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, United States.
          [2 ] ‡School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
          [3 ] §Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
          [4 ] ∥School of Psychology, The University of Sydney, Sydney, New South Wales 2006, Australia.
          [5 ] ⊥Center for Immersive and Simulation-based Learning, Stanford University School of Medicine, Stanford, California 94305, United States.
          [6 ] #Department of Anaesthesia, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
          [7 ] ∇Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia.
          [8 ] ¶School of Medical Sciences, The University of Auckland, Auckland 1142, New Zealand.
          [9 ] ◆Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
          Article
          10.1021/acschemneuro.5b00107
          25921407

          XLR-11, AM-2201, Cannabinoid, JWH-018, PB-22, THC

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