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

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 (CB₁ and CB₂) were evaluated. All ligands showed minimal affinity for CB₁₂ (pK_i <5), although several demonstrated moderate CB₂ binding (pK_i = 5.45-6.99). At 10 ��M none of the compounds produced an effect >50% of CP55,950 at CB₁, while several compounds showed a slightly higher relative efficacy at CB₂. Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.