Abstract
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 10μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1μM) 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 10mg/kg.
Highlights
synthetic cannabinoid receptor agonist (SCRA) represent the largest and most chemically heterogeneous class of new psychoactive substances (NPS), and new examples continue to emerge in drug markets around the world
Of greater concern is the trend for increasing potency of SCRA NPS, with the most recent examples frequently associated with serious adverse effects including myocardial infarction, ischemic stroke, acute kidney injury, tonic-clonic convulsion, coma, and death
Since nothing is known of the chemistry or pharmacology of 5F-PY-PICA and 5F-PY-PINACA, the aim of the present work was to prepare and analytically characterize these emergent SCRAs and several “prophetic” analogues, and to evaluate their cannabinoid receptor affinities and activities in vitro and in vivo
Summary
More than 800 new psychoactive substances (NPS) have been identified in the past decade, including more than 250 synthetic cannabinoid receptor agonists (SCRAs). The earliest SCRA NPS were 1-substituted 3-acylindoles, like JWH-018 (1, Fig. 1), and were based on research compounds with activity at cannabinoid type 1 and 2 (CB1 and CB2, respectively) receptors disclosed by academic laboratories or pharmaceutical companies. As acylindole SCRAs were prohibited in various jurisdictions, newer derivatives not yet subject to legislation such as ABFUBINACA [2] and MDMB-CHMICA [3] appeared to replace them. SCRAs represent the largest and most chemically heterogeneous class of NPS, and new examples continue to emerge in drug markets around the world.8-13Unlike early SCRA NPS, many recent SCRAs have no precedent in the scientific literature when first detected in drug markets, necessitating robust analytical workflows for identification. Even for the most well-studied SCRA NPS, existing data pertain to the activity of these compounds in cellular systems or animal models, with very few human studies reported. Of greater concern is the trend for increasing potency of SCRA NPS, with the most recent examples frequently associated with serious adverse effects including myocardial infarction, ischemic stroke, acute kidney injury, tonic-clonic convulsion, coma, and death.. More than 800 new psychoactive substances (NPS) have been identified in the past decade, including more than 250 synthetic cannabinoid receptor agonists (SCRAs).. The earliest SCRA NPS were 1-substituted 3-acylindoles, like JWH-018 (1, Fig. 1), and were based on research compounds with activity at cannabinoid type 1 and 2 (CB1 and CB2, respectively) receptors disclosed by academic laboratories or pharmaceutical companies.. SCRAs represent the largest and most chemically heterogeneous class of NPS, and new examples continue to emerge in drug markets around the world.. Of greater concern is the trend for increasing potency of SCRA NPS, with the most recent examples frequently associated with serious adverse effects including myocardial infarction, ischemic stroke, acute kidney injury, tonic-clonic convulsion, coma, and death.
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