Pharmacological characterization of novel synthetic opioids (NSO) found in the recreational drug marketplace

NEUROPHARMACOLOGY

卷:134

Article

Baumann, Michael H.¹  Majumdar, Susruta^2,3  Le Rouzic, Valerie^2,3  Hunkele, Amanda^2,3  Uprety, Rajendra^2,3  Huang, Xi Ping⁴  Xu, Jin^2,3  Roth, Bryan L.⁴  Pan, Ying-Xian^2,3  Pasternak, Gavril W.^2,3 

[1] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

[4] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

关键词: Analgesia;    Butyrylfentanyl;    Mu-opioid receptor;    MT-45;    U-47700;   

DOI  :  10.1016/j.neuropharm.2017.08.016

来源: Elsevier

【 摘 要 】

Novel synthetic opioids (NSO) are increasingly encountered in illicit heroin and counterfeit pain pills. Many NSO are resurrected from older biomedical literature or patent applications, so limited information is available about their biological effects. Here we examined the pharmacology of three structurally distinct NSO found in the recreational drug market: N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylbutyramide (butyrylfentanyl), 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and l-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45). Radioligand binding and GTP gamma S functional assays were carried out in cells transfected with murine mu- (MOR-1), delta- (DOR1) or kappa-opioid receptors (KOR-1). Antinociceptive effects were determined using the radiant heat tail flick technique in mice, and opioid specificity was assessed with the mu-opioid antagonist naloxone. Butyrylfentanyl, U-47700 and MT-45 displayed nM affinities at MOR-1, but were less potent than morphine, and had much weaker effects at DOR-1 and KOR-1. All NSO exhibited agonist actions at MOR-1 in the GTP gamma S assay. Butyrylfentanyl and U-47700 were 31- and 12-fold more potent than morphine in the tail flick assay, whereas MT-45 was equipotent with morphine. Analgesic effects were reversed by naloxone and absent in genetically-engineered mice lacking MOR-1. Our findings confirm that butyrylfentanyl, U-47700 and MT-45 are selective MOR-1 agonists with in vitro affinities less than morphine. However, analgesic potencies vary more than 30-fold across the compounds, and in vitro binding affinity does not predict in vivo potency. Taken together, our findings highlight the risks to humans who may unknowingly be exposed to these and other NSO when taking adulterated heroin or counterfeit pain medications. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

【 授权许可】

Free