Vol. 289, Issue 1, 304-311, April 1999

Nitrocinnamoyl and Chlorocinnamoyl Derivatives of Dihydrocodeinone: In Vivo and In Vitro Characterization of µ-Selective Agonist and Antagonist Activity¹

Jay P. McLaughlin, Kevin P. Hill, Qi Jiang, Alice Sebastian, Sydney Archer² and Jean M. Bidlack

Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York (J.P.M., K.P.H., Q.J., J.M.B.); and Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York (A.S., S.A.)

Two 14-p-nitrocinnamoyl derivatives of dihydrocodeinone, 14-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (CACO) and N-cyclopropylmethylnor-14-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (N-CPM-CACO), and the corresponding chlorocinnamoylamino analogs, 14-(p-chlorocinnamoylamino)-7, 8-dihydrocodeinone (CAM) and N-cyclopropylmethylnor-14-(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_max value 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  or  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.