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

Samuel D. Banister*, Richard C. Kevin, Lewis Martin, Axel Adams, Christa Macdonald, Jamie J. Manning, Rochelle Boyd, Michael Cunningham, Marc Y. Stevens, Iain S. McGregor, Michelle Glass, Mark Connor, Roy R. Gerona

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 CB 2 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 hCB 2 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.

Original languageEnglish
Pages (from-to)976-989
Number of pages14
JournalDrug Testing and Analysis
Volume11
Issue number7
Early online date5 Mar 2019
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • 5F-PY-PICA
  • 5F-PY-PINACA
  • cannabinoid
  • mass spectrometry
  • pharmacology

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