Activation of μ-opioid receptors by MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) and its fluorinated derivatives.

background and purposeA fluorinated derivative (2F-MT-45) of the synthetic μ-opioid receptor agonist MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) was recently identified in a seized illicit tablet. While MT-45 is a Class A drug, banned in a number of countries, nothing is known about the pharmacology of 2F-MT-45. This study compares the pharmacology of MT-45, its fluorinated derivatives and two of its metabolites. EXPERIMENTAL APPROACH: We used a β-arrestin2 recruitment assay in CHO cells stably expressing μ receptors to quantify the apparent potencies and efficacies of known (MT-45, morphine, fentanyl and DAMGO) and potential agonists. In addition, the GloSensor protein was transiently expressed to quantify changes in cAMP levels. We measured Ca KEY

resultsThe fluorinated MT-45 derivatives have higher apparent potencies (2F-MT-45: 42 nM) than MT-45 (1.3 μM) for inhibition of cAMP accumulation and β-arrestin2 recruitment (2F-MT-45: 196 nM; MT-45: 23.1 μM). While MT-45 and 2F-MT-45 are poor recruiters of β-arrestin2, they have similar efficacies for reducing cAMP levels as DAMGO. Two MT-45 metabolites displayed negligible potencies as μ receptor agonists, but one, 1,2-diphenylethylpiperazine, inhibited the NMDA receptor with an IC CONCLUSION AND IMPLICATIONS: Fluorinated derivatives of MT-45 are potent μ receptor agonists and this may pose a danger to illicit opioid users. Inhibition of NMDA receptors by a metabolite of MT-45 may contribute to the reported dissociative effects.