Premium
Synthesis and pharmacology of new psychoactive substance 5F‐CUMYL‐P7AICA, a scaffold‐ hopping analog of synthetic cannabinoid receptor agonists 5F‐CUMYL‐PICA and 5F‐CUMYL‐PINACA
Author(s) -
Banister Samuel D.,
Adams Axel,
Kevin Richard C.,
Macdonald Christa,
Glass Michelle,
Boyd Rochelle,
Connor Mark,
McGregor Iain S.,
Havel Christopher M.,
Bright Stephen J.,
Vilamala Mireia Ventura,
Lladanosa Cristina Gil,
Barratt Monica J.,
Gerona Roy R.
Publication year - 2019
Publication title -
drug testing and analysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 54
eISSN - 1942-7611
pISSN - 1942-7603
DOI - 10.1002/dta.2491
Subject(s) - chemistry , cannabinoid , radioligand , synthetic cannabinoids , cannabinoid receptor , cannabinoid receptor agonists , affinities , stereochemistry , receptor , agonist , quinoxaline , combinatorial chemistry , pharmacology , biochemistry , organic chemistry , medicine
Synthetic cannabinoid receptor agonists (SCRAs) are a dynamic class of new psychoactive substances (NPS), with novel chemotypes emerging each year. Following the putative detection of 5F‐CUMYL‐P7AICA in Australia in 2016, the scaffold‐hopping SCRAs 5F‐CUMYL‐PICA, 5F‐CUMYL‐PINACA, and 5F‐CUMYL‐P7AICA were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy, gas chromatography–mass spectrometry (GC–MS), and liquid chromatography–quadrupole time‐of‐flight–MS (LC–QTOF–MS). Since little is known of the pharmacology of 7‐azaindole SCRAs like 5F‐CUMYL‐P7AICA, the binding affinities and functional activities of all compounds at cannabinoid type 1 and type 2 receptors (CB 1 and CB 2 , respectively) were assessed using tritiated radioligand competition experiments and fluorescence‐based plate reader membrane potential assays. Despite CB 1 binding affinities differing by over two orders of magnitude ( K i = 2.95–174 nM), all compounds were potent and efficacious CB 1 agonists (EC 50 = 0.43–4.7 nM), with consistent rank order for binding and functional activity (5F‐CUMYL‐PINACA >5F‐CUMYL‐PICA >5F‐CUMYL‐P7AICA). Additionally, 5F‐CUMYL‐P7AICA was found to exert potent cannabimimetic effects in mice, inducing hypothermia (6°C, 3 mg/kg) through a CB 1 ‐dependent mechanism.