Detection and phase I metabolism of the 7‐azaindole‐derived synthetic cannabinoid 5F‐AB‐P7AICA including a preliminary pharmacokinetic evaluation

Abstract

In June 2018, a 'research chemica'l labeled 'AB‐FUB7AICA' was purchased online and analytically identified as 5F‐AB‐P7AICA, the 7‐azaindole analog of 5F‐AB‐PINACA. Here we present data on structural characterization, suitable urinary consumption markers, and preliminary pharmacokinetic data. Structure characterization was performed by nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry, infrared and Raman spectroscopy. Phase I metabolites were generated by applying a pooled human liver microsome assay (pHLM) to confirm the analysis results of authentic urine samples collected after oral self‐administration of 2.5 mg 5F‐AB‐P7AICA. Analyses of pHLM and urine samples were performed by liquid chromatography−time‐of‐flight mass spectrometry and liquid chromatography–tandem mass spectrometry (LC–MS/MS). An LC–MS/MS method for the quantification of 5F‐AB‐P7AICA in serum was validated. Ten phase I metabolites were detected in human urine samples and confirmed in vitro. The main metabolites were formed by hydroxylation, amide hydrolysis, and hydrolytic defluorination, though – in contrast with most other synthetic cannabinoids – the parent compound showed the highest signals in most urine samples. The compound detection window was more than 45 hours in serum. The concentration‐time profile was best explained by a two‐phase pharmacokinetic model. 5F‐AB‐P7AICA was detected in urine samples until 65 hours post ingestion. Monitoring of metabolite M07, hydroxylated at the alkyl chain, next to parent 5F‐AB‐P7AICA, is recommended to confirm the uptake of 5F‐AB‐P7AICA in urinalysis. It seems plausible that the shift of the nitrogen atom from position 2 to 7 (e.g. 5F‐AB‐PINACA to 5F‐AB‐P7AICA) leads to a lower metabolic reactivity, which might be of general interest in medicinal chemistry.

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

“…The latter finding provides further evidence for the cannabimimetic activity of 19 in vivo, despite having a relatively low affinity for CB 1 and CB 2 (when compared with 55 and 56 ) . Although a study analyzing the in vivo metabolism of 19 , following its oral administration as a 2.5 mg dose in a human subject, has recently been reported, an exploration of the toxicological effects of azaindole SCRAs in humans has yet to appear in the literature.…”

“…36,45 Pharmacological investigation of the effects of 5F-CUMYL-P7AICA (19) in mice has demonstrated its ability to induce hypothermia when injected intraperitoneally (≥ 3 mg/kg). Furthermore, pre-treatment of rodent subjects with 10 mg/kg SR141716 (rimonabant; a known CB 1 T A B L E 1 In vitro CB 1 and CB 2 receptor binding affinity and efficacy data for a series of azaindole constitutional isomers (42-44) compared with WIN-55,212-2 (45) 90 97 Although a study analyzing the in vivo metabolism of 19, following its oral administration as a 2.5 mg dose in a human subject, has recently been reported, 99…”

“…Oxidative metabolism of the heterocyclic scaffold of 5F‐AB‐P7AICA ( 27 ) has not been detected in in vitro (pooled human liver microsome [pHLM] assay) or in vivo (human urine) samples. Although phase I metabolites occurring via oxidation of the heterocyclic core structure of indole and indazole SCRAs are well documented in the literature, 7‐azaindole SCRAs, 19 , 25 , and 27 , may not be subject to such oxidative metabolic processes of their heterocyclic cores . Furthermore, 7‐azaindole SCRA 27 remained unchanged and often presented as the most abundant signal upon LC–MS analysis of both aforementioned in vitro and in vivo samples .…”

“…Although phase I metabolites occurring via oxidation of the heterocyclic core structure of indole and indazole SCRAs are well documented in the literature, 7‐azaindole SCRAs, 19 , 25 , and 27 , may not be subject to such oxidative metabolic processes of their heterocyclic cores . Furthermore, 7‐azaindole SCRA 27 remained unchanged and often presented as the most abundant signal upon LC–MS analysis of both aforementioned in vitro and in vivo samples . Thus, the 7‐azaindole heterocyclic scaffold may confer a degree of metabolic stability to newly emerging SCRAs.…”

“…Giorgetti et al have examined the in vitro and in vivo metabolic profiles of azaindole 27 . Oxidative metabolism of the heterocyclic scaffold of 5F‐AB‐P7AICA ( 27 ) has not been detected in in vitro (pooled human liver microsome [pHLM] assay) or in vivo (human urine) samples.…”