Synthesis of the 5-Fluoro-4-hydroxypentyl Side Chain Metabolites of Synthetic Cannabinoids 5F-APINACA and CUMYL-5F-PINACA

McKinnie, Ryan J.; Darweesh, Tasneam; Zito, Phoebe; Shields, Terrell J.; Trudell, Mark L.

doi:10.1055/s-0037-1609914

Cited by 3 publications

(3 citation statements)

References 14 publications

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“…In method A, the epoxide was opened with TBAF in THF under reflux at 80 C. Product 5 was achieved in a moderate yield of 66%. Another condition (Method B) was also tested using Bu 4 NH 2 F 3 as the fluorinating reagent in a neat reaction at 85 C, which was synthesized according to the description by McKinnie et al [18] The reaction was first attempted at a lower temperature of 60 C to see whether the formation of side products could be suppressed or not, but it was unsuccessful. The temperature was then increased to 85 C. This Method B worked as good as Method A, but the reaction time was longer at a similar temperature.…”

Section: Resultsmentioning

confidence: 99%

“…The crude product was purified with silica gel column chromatography using EtOAc:nheptane (1:2-1:1) to give product 5 (1.62 g, 66%) as a light-yellow sticky oil. 1 Method B: [18] Compound 4 (7.23 g, 21.6 mmol) was combined with tetra-N-butylammonium dihydrogen trifluoride (13.01 g, 43.2 mmol) and the reaction mixture was stirred at 85 C over two nights. The reaction mixture was dissolved in EtOAc (150 mL) and washed with water (2 Â 70 mL).…”

Section: Synthesis Of Benzyl 1-(5-fluoro-4-hydroxypentyl)-1h-indole-3mentioning

confidence: 99%

“…[17] Later in 2018, McKinnie et al developed a synthetic route to achieve the 4OH metabolite of 5F-APINACA and CUMYL-5F-PINACA in better yields but with ten steps. [18] Considering the rapid change in the illicit drug market, a concise synthetic General structural information of synthetic cannabinoids with JWH-018 as an example, where the dotted lines are connected bonds. It was adopted from European Monitoring Center for Drugs and Drug Addiction (EMCDDA) and modified.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of nine potential synthetic cannabinoid metabolites with a 5F-4OH pentyl side chain from a scalable key intermediate

Bopp

Wallgren

et al. 2020

Synthetic Communications

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Benzyl 1-(5-fluoro-4-hydroxypentyl)-1h-indole-3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of nine potential synthetic cannabinoid metabolites with a 5F-4OH pentyl side chain from a scalable key intermediate

Bopp

Wallgren

et al. 2020

Synthetic Communications

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Concise Synthesis of Potential 4-Hydroxy-5-fluoropentyl Side-Chain Metabolites of Four Synthetic Cannabinoids

Wallgren

Rexander

Vestling

et al. 2020

Synlett

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Synthetic cannabinoids are a group of compounds that act on the CB1 receptor and are used illicitly as substitutes for cannabis. Given the rapid and extensive metabolism of synthetic cannabinoids, urinary biomarkers are essential if proof of drug intake is to be obtained in forensic laboratories. To identify good biomarker candidates, the metabolism of synthetic cannabinoids must be studied and reference standards need to be acquired. Studies on the metabolism of synthetic cannabinoids containing a terminally fluorinated pentyl side chain have shown that hydroxylation can occur at the four position of the side chain. This makes the 4-hydroxy-5-fluoropentyl side-chain metabolite a good urinary biomarker for proving intake of the corresponding parent drug, as this compound cannot be formed from its nonfluorinated analogue. Here, a concise synthetic route to the 4-hydroxy-5-fluoropentyl side-chain metabolites of the synthetic cannabinoids STS-135, MAM-2201, AM-2201, and XLR-11 is reported.

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Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Gamage

Farquhar

McKinnie

et al. 2018

J Pharmacol Exp Ther

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Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. Although the structural bases of these compounds are scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB 1 ), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity. Thus, the pharmacology of SC metabolites may be an important component in understanding the in vivo effects of SCs. We examined nine SCs (AB-PINACA, 5F-AB-PINACA, ADB/MDMB-PINACA, 5F-ADB, 5F-CUMYL-PINACA, AMB-PINACA, 5F-AMB, APINACA, and 5F-APINACA) and their hydroxypentyl (either 4-OH or 5-OH) metabolites in [ 3 H]CP55,940 receptor binding and the [ 35 S] GTPgS functional assay to determine the extent to which these metabolites retain activity at cannabinoid receptors. All of the SCs tested exhibited high affinity (,10 nM) and efficacy for hCB 1 and hCB 2 . The majority of the hydroxypentyl metabolites retained full efficacy at hCB 1 and hCB 2 , albeit with reduced affinity and potency, and exhibited greater binding selectivity for hCB 2 . These data suggest that phase I metabolites may be contributing to the in vivo pharmacology and toxicology of abused SCs. Considering this and previous reports demonstrating that metabolites retain efficacy at the hCB 1 receptor, the full pharmacokinetic profiles of the parent compounds and their metabolites need to be considered in terms of the pharmacological effects and time course associated with these drugs.

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Synthesis of the 5-Fluoro-4-hydroxypentyl Side Chain Metabolites of Synthetic Cannabinoids 5F-APINACA and CUMYL-5F-PINACA

Cited by 3 publications

References 14 publications

Synthesis of nine potential synthetic cannabinoid metabolites with a 5F-4OH pentyl side chain from a scalable key intermediate

Synthesis of nine potential synthetic cannabinoid metabolites with a 5F-4OH pentyl side chain from a scalable key intermediate

Concise Synthesis of Potential 4-Hydroxy-5-fluoropentyl Side-Chain Metabolites of Four Synthetic Cannabinoids

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

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