Stereoselective synthesis and receptor binding of conformationally restricted and flexible 2,4-disubstituted 1,3-dioxanes derived from benzomorphans

The key steps in the stereoselective synthesis of the tricyclic aminomethyl derivatives 19 and 20 and the aminoethyl substituted 1,3-dioxanes 24 and 2 5 are nucleophilic addition of aryllithium intermediates to the nitroalkene 13, intramolecular transacetalization of the addition products 15 and 16 ( only for the tricyclic derivatives 19 and 20) and subsequent reduction of t he nitro group. The affinities of the secondary and tertiary amines 19c,d, 20c,d, 24c,d, and 25c,d for the ion channel binding site of the NMDA recept or, for mu-, kappa-, and sigma-receptors have been investigated. In the gro up of tricyclic compounds only 19d shows remarkable sigma-receptor affinity (K-i = 21.6/1.10 mu M). In the 1,3-dioxane series the moderate mu- (K-i = 27.8 mu M) and kappa-receptor affinity (K-i = 36 mu M) as well as the high sigma-receptor affinity (K-i = 3.3 mu M) of the (S,S,S)-configurated methyl amine 24c should be emphasized. The pentan-1-ol 26, the side product isolat ed during the synthesis of 24c, is of particular interest because of its co nsiderable affinity to mu- (K-i = 16.0 mu M), and sigma-receptors (K-i = 14 .5/1.26 mu M). the biphasic competition curves obtained during sigma-recept or binding studies of 19d and 26 (two K-i values) may be explained by diffe rent interaction with sigma-receptor subtypes.