The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F-PY-PICA, 5F-PY-PINACA, and their analogues

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Abstract The structural diversity of synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography–quadrupole time-of-flight–mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at cannabinoid type 1 and type 2 receptors (CB 1 and CB 2 ) were evaluated. All ligands showed minimal affinity for CB 1 (p K i < 5), although several demonstrated moderate CB 2 binding (p K i = 5.45–6.99). At 10 μM none of the compounds produced an effect > 50% of CP55,950 at CB 1 , while several compounds showed a slightly higher relative efficacy at CB 2 . Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.

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