Synthesis and μ-Opioid Activity of the Primary Metabolites of Carfentanil

Hsu, Fu‐Lian; Walz, Andrew J.; Myslinski, James M.; Kong, Ling; Feasel, Michael G.; Goralski, Tyler D. P.; Rose, Tim; Cooper, N. John; Roughley, Neil; Timperley, Christopher M.

doi:10.1021/acsmedchemlett.9b00404

Cited by 14 publications

(6 citation statements)

References 16 publications

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“…Before undertaking the challenge of antibody catalysis of carfentanil’s methyl ester, confirmation was needed that carfentanil’s acid (termed Car acid , see Figure ) would be devoid of any psychotropic activity at physiological concentrations. Interestingly, despite opioid receptor functional activities being documented for carfentanil’s major metabolites, the opioid receptor affinity profile of the Car acid has not been reported . To this end, the Car acid was subjected to radioligand binding assays upon three G-protein-coupled receptor (GPCR) subtypes (μ: MOR, κ: KOR, δ: DOR).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, despite opioid receptor functional activities being documented for carfentanil's major metabolites, the opioid receptor affinity profile of the Car acid has not been reported. 36 To this end, the Car acid was subjected to radioligand binding assays upon three G-protein-coupled receptor (GPCR) subtypes (μ: MOR, κ: KOR, δ: DOR). The primary assay was conducted at a single concentration (10 μM).…”

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confidence: 99%

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Catalytic Antibody Blunts Carfentanil-Induced Respiratory Depression

Lin

Eubanks

Karadkhelkar

et al. 2023

ACS Pharmacol. Transl. Sci.

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Carfentanil, the most potent of the fentanyl analogues, is at the forefront of synthetic opioid-related deaths, second to fentanyl. Moreover, the administration of the opioid receptor antagonist naloxone has proven inadequate for an increasing number of opioid-related conditions, often requiring higher/additional doses to be effective, as such interest in alternative strategies to combat more potent synthetic opioids has intensified. Increasing drug metabolism would be one strategy to detoxify carfentanil; however, carfentanil’s major metabolic pathways involve N-dealkylation or monohydroxylation, which do not lend themselves readily to exogenous enzyme addition. Herein, we report, to our knowledge, the first demonstration that carfentanil’s methyl ester when hydrolyzed to its acid was found to be 40,000 times less potent than carfentanil in activating the μ-opioid receptor. Physiological consequences of carfentanil and its acid were also examined through plethysmography, and carfentanil’s acid was found to be incapable of inducing respiratory depression. Based upon this information, a hapten was chemically synthesized and immunized, allowing the generation of antibodies that were screened for carfentanil ester hydrolysis. From the screening campaign, three antibodies were found to accelerate the hydrolysis of carfentanil’s methyl ester. From this series of catalytic antibodies, the most active underwent extensive kinetic analysis, allowing us to postulate its mechanism of hydrolysis against this synthetic opioid. In the context of potential clinical applications, the antibody, when passively administered, was able to reduce respiratory depression induced by carfentanil. The data presented supports further development of antibody catalysis as a biologic strategy to complement carfentanil overdose reversal.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Catalytic Antibody Blunts Carfentanil-Induced Respiratory Depression

Lin

Eubanks

Karadkhelkar

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…This seems unlikely because valeryl fentanyl is not a known metabolite of fentanyl or of the most common fentanyl analogs, carfentanil, and acetyl fentanyl. 35,36 Valeryl fentanyl is also not an impurity or degradant of fentanyl manufacture. 37 It is also possible that these low values could be because valeryl fentanyl is metabolized into a different compound in the body; however, there is no information about the metabolic pathways of valeryl fentanyl.…”

Section: Discussionmentioning

confidence: 99%

Thirteen Cases of Valeryl Fentanyl in Michigan

Ton

Stevens

Moorman

et al. 2021

Am J Forensic Med Pathol

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In this report, we describe 13 cases of drug overdose in Michigan in which valeryl fentanyl was found in postmortem blood. Valeryl fentanyl is a schedule I opioid that is rarely found in drug overdoses in the United States. Although little data exist on the mortality and morbidity associated with valeryl fentanyl, its molecular structure indicates that it would be less potent than fentanyl.When analyzing blood samples for valeryl fentanyl, samples from peripheral sites were sometimes negative for quantitative levels; however, samples from central sites in the same decedent were positive. This could indicate unique pharmacokinetics for valeryl fentanyl, which could have implications for other fentanyl analogs. Given the paucity of pharmacodynamic information, the prohibition of its use, the potential to buttress law enforcement efforts in monitoring drug trafficking trends, and to determine the efficacy of current regulations, laboratories should test for valeryl fentanyl. When testing for valeryl fentanyl, and likely other fentanyl analogs, the site of sample collection is important: central sources of blood are preferred to peripheral sources.

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“…Following isolation, cAMP accumulation can be quantified via autoradiography. Other cAMP-measuring assays include radioimmunoassays (RIA) (Costa et al, 1992;Bot et al, 1998;Koch et al, 2005), enzyme immunoassays (EIA) (Gharagozlou et al, 2003;Hsu, Mallareddy, et al, 2019;Crowley et al, 2020), (homogeneous) time resolved fluorescence resonance energy transfer (HTRF or TR-FRET) (Nickolls et al, 2011;Schmid et al, 2017;Feasel & Moran, 2018;Hsu, Walz, et al, 2019;Obeng et al, 2020) and AlphaScreen® assays (Cai et al, 2014;Qin et al, 2019), each based on the competition between a cAMP tracer and unlabeled, intracellular cAMP for labeled anti-cAMP antibodies. Luminescence-based assays, such as the cAMP-Glo® assay (Li et al, 2017), have also been used for ligand screening at MOR (Kanamori et al, 2021a(Kanamori et al, , 2021b.…”

Section: Assays Monitoring the G Protein Pathwaymentioning

confidence: 99%