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

BACKGROUND AND PURPOSE: A 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(2+) to investigate whether MT‐45 and its metabolites have effects on GluN1/N2A NMDA receptors stably expressed in Ltk‐ cells. KEY RESULTS: The 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(50) of 29 μM. 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.