Distribution of synthetic opioids in postmortem blood, vitreous humor and brain

Chesser, Rachel; Pardi, Justine; Concheiro, Marta; Cooper, Gail

doi:10.1016/j.forsciint.2019.109999

Cited by 31 publications

(26 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, the development of new methods of analysis is a mandatory task for further studies. The most common methods applied for the detection of opioids in forensic samples are gas chromatography coupled to mass spectrometry (GC–MS), liquid chromatography coupled to mass spectrometry (LC–MS), and liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS), − although thin-layer chromatography (TLC), Raman spectroscopy, and chromatography with detectors other than MS detectors are also applied. , …”

Section: Methods Of Analysismentioning

confidence: 99%

DARK Classics in Chemical Neuroscience: Bucinnazine

Resnik

Brandão

Alves

2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Bucinnazine (1-butyryl-4-cinnamylpiperazine) is a synthetic opioid recently discovered in heroin seized samples in the U.S and in Europe. It was first synthesized in the late 1960s and has been used for the treatment of cancer-associated chronic pain in China for many years. Bucinnazine is one of the most potent compounds among the series of piperazines, which also include other relevant compounds, such as MT-45, AD-1211, and 2-methyl-AP-237, a methylated derivative of bucinnazine. Bucinnazine is considered a μ-selective opioid, binding primarily to the μ-opioid receptor. However, bucinnazine also may share several characteristics with other piperazines, which act primarily on dopamine, serotonin, and norepinephrine neurotransmission. At the present, bucinnazine is not scheduled in the U.S., as it is not a therapeutic choice for the treatment of pain. Nevertheless, with the advent of the cryptocurrency and the easy access of substances on the Darknet, bucinnazine is a real threat to the public health. This review discusses the main aspects of bucinnazine's chemistry, pharmacology, and toxicology and brings attention to the risk of the presence of this opioid in seized samples. Further studies on bucinnazine are still required to better evaluate its toxicity mechanisms, potential for drug−drug interactions, and abuse liability. Such information will be of utmost importance to guide future policies concerning the legal status of bucinnazine in the U.S.

show abstract

Section: Methods Of Analysismentioning

confidence: 99%

DARK Classics in Chemical Neuroscience: Bucinnazine

Resnik

Brandão

Alves

2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Complex fentanyl pharmacokinetics vary across compartments (plasma, cerebrospinal fluid, brain lipid) (Peng and Sandler, 1999). Although fentanyl plasma concentrations are much lower than brain lipid concentrations (Chesser et al, 2019), the high lipid solubility and rapidity of exposure to the CNS after high-dose fentanyl suggests that micromolar K i values for fentanyl binding to non-MORs could be relevant under toxic conditions (Stone and DiFazio, 1988;Yamanoue et al, 1993;Hustveit, 1994).…”

Section: Fentanylmentioning

confidence: 99%

Fentanyl but not Morphine Interacts with Nonopioid Recombinant Human Neurotransmitter Receptors and Transporters

Torralva

Eshleman

Swanson

et al. 2020

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Synthetic opioids, including fentanyl and its analogs, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the United States has increased and contributed to the number one cause of death for adults 18-50 years old. Fentanyl and the heroin metabolite morphine induce respiratory depression that can be treated with the m opioid receptor (MOR) antagonist naloxone. With higher or more rapid dosing, fentanyl, more than morphine, causes chest wall rigidity and can also induce rapid onset laryngospasm. Because non-MORs could mediate differing clinical manifestations, we examined the interactions of fentanyl and morphine at recombinant human neurotransmitter transporters, G protein-coupled receptors, and the N-methyl-Daspartate glutamate receptor. Both drugs were agonists at MOR, k, and d opioid receptors. Morphine had little or no affinity at other human receptors and transporters (K i or IC 50 value .100 mM). However, fentanyl had K i values of 1407 and 1100 nM at a 1A and a 1B adrenoceptor subtypes, respectively, and K i values of 1049 and 1670 nM at dopamine D4.4 and D1 receptor subtypes, respectively; it also blocked [ 3 H]neurotransmitter uptake by the vesicular monoamine transporter 2 (IC 50 = 911 nM). Pharmacokinetic models indicate that these Ki and IC 50 values are pharmacologically relevant. Fentanyl had little affinity for other receptors or transporters. Thus, noradrenergic disposition at specific receptor subtypes in relevant organs may play a role in respiratory and cardiothoracic effects of fentanyl. Data suggest that less selective fentanyl receptor pharmacology could play a role in the different clinical effects of morphine compared with fentanyl, including fentanyl-induced deaths after illicit use. SIGNIFICANCE STATEMENTThe synthetic opioid fentanyl induces different clinical effects, including rapid onset muscular rigidity, vocal cord closure, and rapid death, than the heroin metabolite morphine. Our data indicate for the first time that the two drugs have very different effects at recombinant human neurotransmitter receptors and transporters that might explain those clinical differences.

show abstract

“…In the mid- to late 1970s, there was significant effort to identify opioid analgesics possessing chemotypes and pharmacophores structurally distinct from morphine ( 1 ) and heroin ( 2 ), the so-called novel synthetic opioids (NSO) (Figure ). − At the time, research efforts also coined such novel chemotypes as new psychoactive substances (NPS), as these compounds were created via synthetic chemistry in the laboratory to mimic the pharmacology of controlled substances. − Fentanyl ( 3 ) and MT-45 ( 4 ) are examples of NSO research that developed compounds with activity far exceeding that of 1 (e.g., 3 is 100× more potent than morphine), and that are now dangerous illicit drugs of abuse with extremely high mortality rates. ,− A novel chemotype of opioid analgesics, based on a cyclohexyl diamine scaffold and named AH-7921 ( 5 ), was patented in 1976 by researchers at Allen and Hanburys Ltd. in the United Kingdom. − AH-7921 was slightly less potent than morphine when dosed orally (∼90% of 1 ), but it demonstrated both analgesic efficacy and adverse side effects comparable to 1. , While it was never advanced into human clinical testing, its ease of synthesis, and readily available patent procedures, led to its clandestine production and availability for illicit use. − Since 2012, it has been available for purchase on the Internet as a “research chemical” or “legal opioid” under the name doxylam. ,, It has been present in “synthetic cannabis” and counterfeit pain medications, associated with numerous fatalities.…”

Section: Introductionmentioning

confidence: 99%

“…Patented by the Upjohn company in 1976, Szmuszkovicz and co-workers discovered U-47700, trans racemic 3,4-dichloro- N -2-(dimethylamino)cyclohexyl- N -methyl benzamide ( 6 ), though the literature now assigns U-47700 as the ( R , R )-diastereomer shown, 3,4-dichloro- N -((1 R ,2 R )-2-(dimethylamino)cyclohexyl)- N -methyl benzamide. , U-47700 was a potent μ-opioid, MOR, agonist with in vivo activity 7.5–12-fold greater than morphine ( vide infra ), but it never advanced to the clinic nor was studied in man. ,− As a result, there is scant drug metabolism and pharmacokinetics (DMPK) data for the molecule, except that from postmortem overdose victims. ,, Szmuszkovicz and co-workers did, however, conduct a detailed structure–activity relationship (SAR) study around 6 , which resulted in key tool compounds, such as U-50488 ( 7 ), U-51754 ( 8 ), and U-62066 ( 9 ), to selectively study the κ-opioid receptor (KOR). ,,− Interestingly, the switch from μ-selective agonist to κ-selective agonist was homologation of the 3,4-dichlorobenzamide to the 3,4-dichlorophenyl acetamide (cf. 6 – 8 ) (Figure ).…”

Section: Introductionmentioning

confidence: 99%

DARK Classics in Chemical Neuroscience: U-47700

Kyei-Baffour

Lindsley

2020

ACS Chem. Neurosci.

View full text Add to dashboard Cite

U-47700, 3,4-dichloro-N-((1R,2R)-2-(dimethylamino)cyclohexyl)-N-methyl benzamide, is a novel synthetic opioid (NSO), discovered by the Upjohn company in the late 1970s. With potent in vivo activity, ∼10-times greater than that of morphine, U-47700 has become a drug of widespread abuse due to its ease of synthesis and, until recently, lack of robust detection methods by law enforcement. U-47700 has been found in counterfeit oxycodone tablets and is a key ingredient in “gray death.” Due to its emergence worldwide in the past 5 years, it is now a Schedule I drug in the United States and similarly designated around the world; moreover, at autopsy, U-47700 was found to have contributed to the death of the pop artist Prince. This Review will capture the >40 year history of U-47700 and go in-depth regarding the synthesis, medicinal chemistry, in vitro/in vivo pharmacology, drug metabolism (from postmortem overdose cases), and societal impact of this DARK Classic in chemical neuroscience.

show abstract

Distribution of synthetic opioids in postmortem blood, vitreous humor and brain

Cited by 31 publications

References 37 publications

DARK Classics in Chemical Neuroscience: Bucinnazine

DARK Classics in Chemical Neuroscience: Bucinnazine

Fentanyl but not Morphine Interacts with Nonopioid Recombinant Human Neurotransmitter Receptors and Transporters

DARK Classics in Chemical Neuroscience: U-47700

Contact Info

Product

Resources

About