The stereoselective kappa-opioid receptor antagonist Mr2266 does not exhibit stereoselectivity as an antagonist at the orphan opioid (ORL1) receptor

Mr 2266 [(-)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzom orphan] is an antagonist at kappa-opioid receptors and at ORL, receptors as well. The aim of our study was to examine whether the known stereoselectiv e antagonism of Mr 2266 at kappa-opioid receptors also extends to ORL, rece ptors. In mouse brain cortex membranes, the binding of the ORL, receptor ag onist [H-3]nociceptin was equipotently inhibited by Mr 2266 and its enantio mer Mr 2267 (pK(i) 4.82 and 5.14, respectively), whereas the binding of the kappa-opioid receptor agonist [H-3]U-69,593 was inhibited by Mr 2266 more potently (pK(i) 9.11) than by its enantiomer Mr 2267 (pK(i) 7.15). In mouse brain cortex slices preincubated with [H-3]noradrenaline, the concentratio n-response curve of nociceptin for inhibition of the electrically evoked ov erflow of tritium was equipotently shifted to the right by Mr 2266 and Mr 2 267 (pA(2) 5.77 and 5.64, respectively). On the other hand, the inhibitory effect of U-69,593 on the electrically evoked over flow of tritium in guine a-pig brain cortex slices preincubated with [H-3]noradrenaline was more pot ently antagonized by Mr 2266 (pA(2) 8.81) than by Mr 2267 (pA(2) 7.15). The se data show that the stereoselective antagonism of Mr 2266 at kappa-opioid receptors does not extend to ORL, receptors.