Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors

Eshleman, Amy J.; Nagarajan, Shanthi; Wolfrum, Katherine M.; Reed, John; Nilsen, Aaron; Torralva, Randy; Janowsky, Aaron

doi:10.1016/j.bcp.2020.114293

Cited by 37 publications

(60 citation statements)

References 63 publications

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“…The binding affinity to the µ-opioid receptor was reported to be 17 nM by Hassanien et al. ( 7 ) and 0.56 nM by Eshleman ( 6 ), ∼11 times and 4.1 times less potent than fentanyl. Using the GTPγS assay, Hassanien et al.…”

Section: Introductionmentioning

confidence: 97%

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Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Kronstrand

Åstrand

Watanabe

et al. 2021

Journal of Analytical Toxicology

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Methoxyacetylfentanyl is one of many fentanyl analogs available as new psychoactive substances. It have been encountered in both the European Union and the United States, and existing literature suggest that methoxyacetylfentanyl is around 3 to 5-fold less potent than fentanyl. The aim of the present work was to combine case information with blood concentrations and abundance of urinary metabolites to investigate the importance of these parameters for toxicological interpretation. Quantification of methoxyacetylfentanyl in femoral blood was performed by LC-MS/MS and urinary metabolites were analyzed by LC-QTOF-MS with and without hydrolysis with β-glucuronidase/arylsulfatase. For confirmation of identified metabolites, methoxyacetylfentanyl was incubated with hepatocytes for up to 5 hours and analyzed with the same method as the urine samples. In eleven postmortem cases (27 to 41 years old and including one female) methoxyacetylfentanyl was reported in femoral blood. The cause of death was intoxication by methoxyacetylfentanyl alone or in combination with other drugs in all but one case, where death was attributed to acute complications of an underlying heart disease but with possible contribution from methoxyacetylfentanyl. In total, 27 urinary metabolites were found, including eight glucuronides. Major biotransformations were O-demethylation, dealkylation to form the nor-metabolite, mono- and dihydroxylations of the phenethyl moiety, as well as combinations thereof. The most abundant metabolites in hydrolyzed urine included O-desmethyl-, O-desmethyl-phenethyl-hydroxy-, O-desmethyl-phenethyl-hydroxymethoxy- and nor-methoxyacetylfentanyl.Differences in the abundance of methoxyacetylfentanyl and its major metabolites could be interpreted to indicate fatal intoxications in abstinent or chronic users. We postulate that urinary concentrations of methoxyacetylfentanyl and two metabolites, in combination with the methoxyacetylfentanyl concentration in femoral blood, might be good indicators of the time between administration and death as well as prior use.

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Section: Introductionmentioning

confidence: 97%

“…Methoxyacetylfentanyl has been characterized as a µ-opioid receptor agonist both in vitro ( 6–8 ) and in vivo ( 2 , 9–13 ). The binding affinity to the µ-opioid receptor was reported to be 17 nM by Hassanien et al.…”

Section: Introductionmentioning

confidence: 99%

Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Kronstrand

Åstrand

Watanabe

et al. 2021

Journal of Analytical Toxicology

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“…fentanyl were only partially effective (~60%) at stimulating 35 S-GTPγ binding at MOR suggesting potential partial agonism for these two compounds in the in vitro assay. However, when tested as inhibitors of 3 H-DAMGO in the MOR-mediated 35 S-GTPγ binding assay, no evidence of antagonistic activity in the nanomolar range was observed for acetyl fentanyl and butyryl fentanyl which would be expected of partial agonists (Eshleman et al, 2020). In vivo, acetyl fentanyl and butyryl fentanyl were less potent than fentanyl but fully effective in the acetic acid writhing test in mice (Higashikawa and Suzuki, 2008) similar to the results observed in the present study using the warm-water, tail-withdrawal procedure in rats.…”

Section: Discussionmentioning

confidence: 95%

“…In 3 H-DAMGO radioligand binding assays, Ki values for acetyl fentanyl and butyryl fentanyl were 4.28 and 0.405 nM, respectively, compared to 0.252 nM for morphine and 0.135 nM for fentanyl. Acetyl fentanyl and butyryl fentanyl were less potent than fentanyl to stimulate 35 S-GTPγS binding at MOR (Eshleman et al, 2020). Interestingly, both acetyl fentanyl and butyryl This article has not been copyedited and formatted.…”

Section: Discussionmentioning

confidence: 99%

“…Different opioids activate mu opioid receptor (MOR), kappa opioid receptor (KOR), and delta opioid receptor (DOR) to various degrees to produce such effects as analgesia, constipation, respiratory depression, and euphoria although the predominant mechanism for these effects is activation through the MOR (Williams et al, 2013). In radioligand binding studies, the opioid fentanyl has high affinity and selectivity for MOR (Costa et al, 1992;Eshleman et al, 2020). Fentanyl has a high lipophilicity which allows rapid diffusion through the blood brain barrier for a fast onset of action.…”

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confidence: 99%

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Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats

Walker

Chambers

Korber

et al. 2021

J Pharmacol Exp Ther

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Compounds with novel or fentanyl-like structures continue to appear on the illicit drug market and have been responsible for fatalities, yet there are limited preclinical pharmacological data available to evaluate the risk of these compounds to public health. The purpose of the present study was to examine acetyl fentanyl, butyryl fentanyl, AH-7921, MT-45, W-15, and W-18 for their relative potency to reference opioids and their susceptibility to naltrexone antagonism using the 55 o C warm-water, tail-withdrawal assay of antinociception and a morphine drug discrimination assay in male, Sprague Dawley rats. In the antinociception assay, groups of 8 rats per drug were placed into restraining tubes, their tails were immersed into 40 o or 55 o C water, and the latency for tail withdrawal was measured with a cutoff time of 15 sec. In the drug discrimination assay, rats (n=11) were trained to discriminate between 3.2 mg/kg morphine and saline, s.c., in a two-choice, drug discrimination procedure under a fixed ratio-5 schedule of sucrose pellet delivery. Morphine, fentanyl, and four of the synthetic opioids dose-dependently produced antinociception and fully substituted for morphine in the drug discrimination assay with the following rank order of potency: fentanyl>butyryl fentanyl>acetyl fentanyl>AH-7921>MT45>morphine. All drugs that produced antinociception or morphine-like discriminative stimulus effects were blocked by naltrexone. W-15 and W-18 did not show antinociceptive or morphine-like discriminative stimulus effects at the doses tested supporting a lack of opioid activity for these two compounds. These findings suggest that butyryl fentanyl, acetyl fentanyl, AH-7941, and MT-45 have abuse liability like other opioid agonists.

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Investigation of the μ‐ and κ‐opioid receptor activation by eight new synthetic opioids using the [³⁵S]‐GTPγS assay: U‐47700, isopropyl U‐47700, U‐49900, U‐47931E, N‐methyl U‐47931E, U‐51754, U‐48520, and U‐48800

Otte

Wilde

Auwärter

et al. 2022

Drug Testing and Analysis

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In 2009, new synthetic opioids appeared on the new psychoactive substances market. This class of new psychoactive substances generally poses a health risk due to the high affinity and potency of most of these compounds for the opioid receptors. It is known that overdoses can lead to respiratory depression and result in death. However, for many new synthetic opioids, data on toxicological and toxicokinetic properties are scarce. In the present study, eight U-opioids were investigated for their structure activity relationships at the μand κ-opioid receptors using a [ 35 S]-GTPγS

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Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors

Cited by 37 publications

References 63 publications

Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats

Investigation of the μ‐ and κ‐opioid receptor activation by eight new synthetic opioids using the [³⁵S]‐GTPγS assay: U‐47700, isopropyl U‐47700, U‐49900, U‐47931E, N‐methyl U‐47931E, U‐51754, U‐48520, and U‐48800

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Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors

Cited by 37 publications

References 63 publications

Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Circumstances, Postmortem Findings, Blood Concentrations and Metabolism in a Series of Methoxyacetylfentanyl-Related Deaths

Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats

Investigation of the μ‐ and κ‐opioid receptor activation by eight new synthetic opioids using the [35S]‐GTPγS assay: U‐47700, isopropyl U‐47700, U‐49900, U‐47931E, N‐methyl U‐47931E, U‐51754, U‐48520, and U‐48800

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Investigation of the μ‐ and κ‐opioid receptor activation by eight new synthetic opioids using the [³⁵S]‐GTPγS assay: U‐47700, isopropyl U‐47700, U‐49900, U‐47931E, N‐methyl U‐47931E, U‐51754, U‐48520, and U‐48800