Etsuo Ohshima

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.

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.

Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 1

A series of 11-[[2-[(arylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acids and related derivatives were synthesized. The compounds were tested for their antagonizing effects on guinea pig platelet TXA2/PGH2 receptors. Structure-activity relationships are discussed. (+/-)-11-[[2-[(Styrylsulfonyl)amino]ethyl]-thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acid (41) and (+/-)-11-[[2-[(phenylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]thiepin-2-carboxylic acid (4af) were the most promising compounds with K(i) values of 6.5 +/- 0.29 and 3.7 +/- 0.31 nM, respectively, for the TXA2/PGH2 receptor. These compounds also significantly inhibited U-46619-induced guinea pig platelet aggregation ex vivo (10 mg/kg po). Compound 41 was resolved into its optically active form. The (-)-isomer was 60-fold more potent than the (+)-isomer in the TXA2/PGH2 receptor binding assay. Some compounds tested in this study showed both TXA2/PGH2 receptor antagonizing and TXA2 synthase inhibitory effects.