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 25 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 the 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 receptor, for mu-, kappa-, and sigma-receptors have been investigated. In the group of tricyclic compounds only 19d shows remarkable sigma-receptor affinity (Ki = 21.6/1.10 microM). In the 1,3-dioxane series the moderate mu- (Ki = 27.8 microM) and kappa-receptor affinity (Ki = 36 microM) as well as the high sigma-receptor affinity (Ki = 3.3 microM) of the (S,S,S)-configurated methylamine 24c should be emphasized. The pentan-1-ol 26, the side product isolated during the synthesis of 24c, is of particular interest because of its considerable affinity to mu- (Ki = 16.0 microM), kappa- (Ki = 2.8 microM), and sigma-receptors (Ki = 14.5/1.26 microM). The biphasic competition curves obtained during sigma-receptor binding studies of 19d and 26 (two Ki values) may be explained by different interaction with sigma-receptor subtypes.
Wünsch
B
B
Pharmazeutisches Institut der Universität Freiburg, Germany.
Bauschke
G
G
Diekmann
H
H
Höfner
G
G
D000588:Amines / Q000138:chemical synthesis; D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000737:chemistry; D001667:Binding, Competitive; D002417:Cattle; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D001575:Benzomorphans; D004146:Dioxanes; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid