School of Chemistry, The University of Sydney, NSW, Australia.
Department of Pathology, Stanford University, CA, USA.
Drug Test Anal. 2019 Jul;11(7):976-989. doi: 10.1002/dta.2583. Epub 2019 May 8.
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 (hCB ) or type 2 (hCB ), all analogs showed minimal affinity for CB (pK < 5), although several demonstrated moderate CB binding (pK 5.45-6.99). In fluorescence-based membrane potential assays using AtT20-hCB or -hCB cells, none of the compounds (at 10 μM) produced an effect >50% of the classical cannabinoid agonist CP55,940 (at 1 μM) at hCB , although several showed slightly higher relative efficacy at hCB . Expansion of the pyrrolidine ring of 5F-PY-PICA to an azepane (8) conferred the greatest hCB affinity (pK 6.99) and activity (pEC 7.54, E 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.
5F-PY-PICA 和 5F-PY-PINACA 是在 2015 年被鉴定为潜在的合成大麻素受体激动剂（SCRA）新型精神活性物质（NPS）的吡咯烷基 1-（5-氟戊基）吲哚（氮）唑-3-甲酰胺。5F-PY-PICA、5F-PY-PINACA 及其 1-烷基取代基变化、吡咯烷环收缩、扩张或断裂的类似物通过核磁共振（NMR）光谱和液相色谱-四极杆飞行时间质谱（LC-QTOF-MS）进行了合成和表征。在与表达人大麻素受体 1 型（hCB1）或 2 型（hCB2）的 HEK293 细胞的竞争性结合实验中，所有类似物对 CB 的亲和力均较小（pK <5），尽管有几个类似物表现出中等 CB 结合（pK 5.45-6.99）。在使用 AtT20-hCB1 或 -hCB2 细胞的基于荧光的膜电位测定中，在 hCB1 中，没有一种化合物（在 10 μM 时）产生的作用超过经典大麻素激动剂 CP55940（在 1 μM 时）的 50%，尽管有几个类似物在 hCB2 中显示出略高的相对功效。5F-PY-PICA 的吡咯烷环扩展到氮杂环庚烷（8）赋予该系列化合物最大的 hCB1 亲和力（pK 6.99）和活性（pEC 7.54，E 72%）。与使用无线电遥测术在体内评估的其他 SCRA NPS 不同，5F-PY-PICA 和 5F-PY-PINACA 在高达 10 mg/kg 的剂量下，在小鼠中没有产生大麻样效应（体温过低、心动过缓）。
