Probes for Narcotic Receptor Mediated Phenomena. 37.1 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

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 a 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 κ-receptor antagonists in the [ 35 S]GTPγS assay. We synthesized the N -phenethyl-substituted oxide-bridged phenylmorphans in the ortho - and para -d oxide-bridged phenylmorphan a 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 .