• DOI:10.1007/s002100000266
• Corpus ID: 10459734

Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor

@article{Gillen2000AffinityPA,
  title={Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor},
  author={Clemens Gillen and Michael Haurand and D. Kobelt and Stephan Wnendt},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
  year={2000},
  volume={362},
  pages={116-121}
}

• C. Gillen, M. Haurand, +1 author S. Wnendt
• Published 18 July 2000
• Biology, Chemistry
• Naunyn-Schmiedeberg's Archives of Pharmacology

Abstract. The present study was conducted to characterise the centrally active analgesic drug tramadol hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride] and its metabolites M1, M2, M3, M4 and M5 at the cloned human µ-opioid receptor. Membranes from stably transfected Chinese hamster ovary (CHO) cells were used to determine the four parameters of the ligand-receptor interaction: the affinity of (±)-tramadol and its metabolites was determined by competitive inhibition of [3H]naloxone binding under high and low salt conditions. The agonist-induced stimulation of [35S]GTPγS binding permits the measurement of potency (EC50), efficacy (Emax = maximal stimulation) and relative intrinsic efficacy (effect as a function of receptor occupation). The metabolite (+)-M1 showed the highest affinity (Ki=3.4 nM) to the human µ-opioid receptor, followed by (±)-M5 (Ki=100 nM), (-)-M1 (Ki=240 nM) and (±)-tramadol (Ki=2.4 µM). The [35S]GTPγS binding assay revealed an agonistic activity for the metabolites (+)-M1, (-)-M1 and (±)-M5 with the following rank order of intrinsic efficacy: (+)-M1>(±)-M5>(-)-M1. The metabolites (±)-M2, (±)-M3 and (±)-M4 displayed only weak affinity (Ki>10 µM) and had no stimulatory effect on GTPγS binding. These data indicate that the metabolite (+)-M1 is responsible for the µ-opioid-derived analgesic effect.