Abstract

Two 14β-p-nitrocinnamoyl derivatives of dihydrocodeinone, 14β-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (CACO) andN-cyclopropylmethylnor-14β-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (N-CPM-CACO), and the corresponding chlorocinnamoylamino analogs, 14β-(p-chlorocinnamoylamino)-7, 8-dihydrocodeinone (CAM) andN-cyclopropylmethylnor-14β-(p-chlorocinnamoylamino)-7,8-dihydrocodeinone (MC-CAM), were tested in opioid receptor binding assays and the mouse tail-flick test to characterize the opioid affinity, selectivity, and antinociceptive properties of these compounds. In competition binding assays, all four compounds bound to the μ opioid receptor with high affinity. When bovine striatal membranes were incubated with any of the four dihydrocodeinones, binding to the μ receptor was inhibited in a concentration-dependent, wash-resistant manner. Saturation binding experiments demonstrated that the wash-resistant inhibition of μ binding was due to a decrease in the B_maxvalue for the binding of the μ-selective peptide [³H][d-Ala², MePhe⁴,Gly(ol)⁵] enkephalin and not a change in the K_d value, suggesting an irreversible interaction of the compounds with the μ receptor. In the mouse 55°C warm water tail-flick test, both CACO and N-CPM-CACO acted as short-term μ-selective agonists when administered by i.c.v. injection, whereas CAM and MC-CAM produced no measurable antinociception at doses up to 30 nmol. Pretreatment of mice for 24 h with any of the four dihydrocodeinone derivatives produced a dose-dependent antagonism of antinociception mediated by the μ but not the δ or κ receptors. Long-term antagonism of morphine-induced antinociception lasted for at least 48 h after i.c.v. administration. Finally, shifts in the morphine dose-response lines after 24-h pretreatment with the four dihydrocodeinone compounds suggest that the nitrocinnamoylamino derivatives may produce a greater magnitude long-term antagonism of morphine-induced antinociception than the chlorocinnamoylamino analogs.