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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• 作者：Samuel D. Banister ; Jordyn Stuart ; Richard C. Kevin ; Amelia Edington ; Mitchell Longworth ; Shane M. Wilkinson ; Corinne Beinat ; Alexandra S. Buchanan ; David E. Hibbs ; Michelle Glass ; Mark Connor ; Iain S. McGregor ; Michael Kassiou
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：August 19, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：1445-1458
• 全文大小：666K
• ISSN：1948-7193

文摘

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鈥?959 nM) and CB₂ (EC₅₀ = 6.5鈥?06 nM) receptors, with the fluorinated analogues generally showing increased CB₁ receptor potency (鈭?鈥? 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鈥?0 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).