Activation of μ opioid receptors by MT‐45 and its fluorinated derivatives

BACKGROUND AND PURPOSE: A fluorinated derivative (2F-MT-45) of the synthetic mu-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 beta-arrestin2 recruitment assay in CHO cells stably expressing mu 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(2+) to investigate whether MT-45 and its metabolites have effects on NR1A/NR2A NMDA receptors stably expressed in Ltk- cells. KEY RESULTS: The fluorinated MT-45 derivatives have higher apparent potencies (2-F-MT-45: 42 nM) than MT-45 (1.3 muM) for inhibition of cAMP accumulation and beta-arrestin2 recruitment (2-F-MT-45: 196 nM; MT-45: 23.1 muM). While MT-45 and 2F-MT-45 are poor recruiters of beta-arrestin2, they have similar efficacies for reducing cAMP levels as DAMGO. Two MT-45 metabolites displayed negligible potencies as mu receptor agonists, but one, 1,2-diphenylethylpiperazine, inhibited the NMDA receptor with an IC50 of 29 muM. CONCLUSION AND IMPLICATIONS: Fluorinated derivatives of MT-45 are potent mu 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.