The stereoselective κ-opioid receptor antagonist Mr 2266 does not exhibit stereoselectivity as an antagonist at the orphan opioid (ORL1) receptor

Abstract

Mr 2266 [(-)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2’-hydroxy-6,7-benzomorphan] is an antagonist at κ-opioid receptors and at ORL₁ receptors as well. The aim of our study was to examine whether the known stereoselective antagonism of Mr 2266 at κ-opioid receptors also extends to ORL₁ receptors. In mouse brain cortex membranes, the binding of the ORL₁ receptor agonist [³H]nociceptin was equipotently inhibited by Mr 2266 and its enantiomer Mr 2267 (pK _i 4.82 and 5.14, respectively), whereas the binding of the κ-opioid receptor agonist [³H]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 [³H]noradrenaline, the concentration-response curve of nociceptin for inhibition of the electrically evoked overflow of tritium was equipotently shifted to the right by Mr 2266 and Mr 2267 (pA ₂ 5.77 and 5.64, respectively). On the other hand, the inhibitory effect of U-69,593 on the electrically evoked overflow of tritium in guinea-pig brain cortex slices preincubated with [³H]noradrenaline was more potently antagonized by Mr 2266 (pA ₂ 8.81) than by Mr 2267 (pA ₂ 7.15). These data show that the stereoselective antagonism of Mr 2266 at κ-opioid receptors does not extend to ORL₁ receptors.