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

5F‐PY‐PICA and 5F‐PY‐PINACA are pyrrolidinyl 1‐(5‐fluoropentyl)ind (az)ole‐3‐carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F‐PY‐PICA, 5F‐PY‐PINACA, and analogs featuring variation of the 1‐alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–quadrupole time‐of‐flight–mass spectrometry (LC–QTOF–MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB₁) or type 2 (hCB₂), all analogs showed minimal affinity for CB₁ (pK_i < 5), although several demonstrated moderate CB₂ binding (pK_i 5.45–6.99). In fluorescence‐based membrane potential assays using AtT20‐hCB₁ or ‐hCB₂ cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB₁, although several showed slightly higher relative efficacy at hCB₂. Expansion of the pyrrolidine ring of 5F‐PY‐PICA to an azepane ( 8 ) conferred the greatest hCB₂ affinity (pK_i 6.99) and activity (pEC₅₀ 7.54, E_max 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F‐PY‐PICA and 5F‐PY‐PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.