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.
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).
†Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, United States.|‡School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
Samuel D
SD
Banister
§Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Jordyn
J
Stuart
∥School of Psychology, The University of Sydney, Sydney, New South Wales 2006, Australia.
Richard C
RC
Kevin
§Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Amelia
A
Edington
‡School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
Mitchell
M
Longworth
‡School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
Shane M
SM
Wilkinson
†Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, United States.|‡School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
Corinne
C
Beinat
⊥Center for Immersive and Simulation-based Learning, Stanford University School of Medicine, Stanford, California 94305, United States.|#Department of Anaesthesia, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
Alexandra S
AS
Buchanan
∇Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales 2006, Australia.
David E
DE
Hibbs
¶School of Medical Sciences, The University of Auckland, Auckland 1142, New Zealand.
Michelle
M
Glass
§Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Mark
M
Connor
∥School of Psychology, The University of Sydney, Sydney, New South Wales 2006, Australia.
Iain S
IS
McGregor
‡School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.|◆Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
Michael
M
Kassiou
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015198:Designer Drugs / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D013686:Telemetry
C586710:(1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone; C582337:1-(5-fluoropentyl)-3-(1-naphthoyl)indole; C000590832:1-pentyl-1H-indole-3-carboxylic acid 8-quinolinyl ester; C571130:CNR1 protein, human; C588309:CNR2 protein, human; D002186:Cannabinoids; D015198:Designer Drugs; D007211:Indoles; C000603149:N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide; D009281:Naphthalenes; D011804:Quinolines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C552597:1-pentyl-3-(1-naphthoyl)indole; C585106:XLR-11; D000218:Adamantane
AM-2201; Cannabinoid; JWH-018; PB-22; THC; XLR-11