Baptista-Hon Daniel T, Smith Mark, Singleton Samuel, Antonides Lysbeth H, Nic Daeid Niamh, McKenzie Craig, Hales Tim G
Institute of Academic Anaesthesia, Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
Leverhulme Research Centre for Forensic Science, School of Science and Engineering, University of Dundee, Dundee, UK.
Br J Pharmacol. 2020 Aug;177(15):3436-3448. doi: 10.1111/bph.15064. Epub 2020 May 13.
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.
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 to investigate whether MT-45 and its metabolites have effects on GluN1/N2A NMDA receptors stably expressed in Ltk- cells.
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 of 29 μM.
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.
合成的μ阿片受体激动剂MT - 45（1 - 环己基 - 4 -（1,2 - 二苯乙基）哌嗪）的一种氟化衍生物（2F - MT - 45）最近在查获的非法片剂中被发现。虽然MT - 45是一种A类药物，在许多国家被禁止，但对2F - MT - 45的药理学特性却一无所知。本研究比较了MT - 45、其氟化衍生物及其两种代谢物的药理学特性。
我们在稳定表达μ受体的CHO细胞中使用β - arrestin2募集试验来量化已知（MT - 45、吗啡、芬太尼和DAMGO）和潜在激动剂的表观效力和效能。此外，瞬时表达GloSensor蛋白以量化cAMP水平的变化。我们测量了钙离子，以研究MT - 45及其代谢物是否对稳定表达于Ltk - 细胞中的GluN1/N2A NMDA受体有影响。
氟化的MT - 45衍生物在抑制cAMP积累和β - arrestin2募集方面比MT - 45具有更高的表观效力（2F - MT - 45：42 nM）（2F - MT - 45：196 nM；MT - 45：23.1 μM）。虽然MT - 45和2F - MT - 45是β - arrestin2的低效募集剂，但它们在降低cAMP水平方面与DAMGO具有相似的效能。两种MT - 45代谢物作为μ受体激动剂的效力可忽略不计，但其中一种，1,2 - 二苯乙基哌嗪，以29 μM的IC50抑制NMDA受体。
MT - 45的氟化衍生物是强效的μ受体激动剂，这可能对非法阿片类药物使用者构成危险。MT - 45的一种代谢物对NMDA受体的抑制作用可能导致了所报道的分离效应。
