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 (pKi < 5), although several demonstrated moderate CB2 binding (pKi 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 (pKi 6.99) and activity (pEC50 7.54, Emax 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.
Keywords: 5F-PY-PICA; 5F-PY-PINACA; cannabinoid; mass spectrometry; pharmacology.
© 2019 John Wiley & Sons, Ltd.