SYNTHESES OF NOVEL PYRIDAZINOMORPHINANS BY INVERSE ELECTRON DEMAND CYCLOADDITION AND THEIR BINDING TO MU-RECEPTORS AND KAPPA-RECEPTORS

A number of novel pyridazinomorphinans have been synthesized by the in verse electron demand Diels-Alder reaction of various 3,6-disubstitute d 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and w ith codeinone. Reduction of some of the pyridazinomprphinans did not f urnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyr idazino- or pyrrolomorphinans. The structures of all new compounds wer e assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 1 1a, and 16 have been evaluated for their affinity at mu and kappa opio id receptors in radioligand binding assays. Their ability to inhibit [ H-3]DAMGO binding at mu and [H-3]U 69.593 binding at kappa receptors, respectively as compared to codeine has been found to be lower.