Probes for Narcotic Receptor Mediated Phenomena. 37. Synthesis and Opioid Binding Affinity of the Final Pair of Oxide-Bridged Phenylmorphans, the Ortho- and Para-b-Isomers and Their N-Phenethyl Analogues, and the Synthesis of the N-Phenethyl Analogues of the Ortho- and Para-d-Isomers

Abstract

In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphans 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent kappa-receptor antagonists in the [(35)S]GTPgammaS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d-oxide-bridged phenylmorphan series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47.