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Stereoselective Synthesis and Receptor Binding of Conformationally Restricted and Flexible 2,4‐Disubstituted 1,3‐Dioxanes Derived from Benzomorphans
Author(s) -
Wünsch Bernhard,
Bauschke Gerd,
Diekmann Heike,
Höfner Georg
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199912)332:12<413::aid-ardp413>3.0.co;2-0
Subject(s) - chemistry , stereochemistry , stereoselectivity , tricyclic , receptor , intramolecular force , methylamine , chemical synthesis , biochemistry , in vitro , catalysis
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 μ‐, κ‐, and σ‐receptors have been investigated. In the group of tricyclic compounds only 19d shows remarkable σ‐receptor affinity ( K i = 21.6/1.10 μM). In the 1,3‐dioxane series the moderate μ‐ ( K i = 27.8 μM) and κ‐receptor affinity ( K i = 36 μM) as well as the high σ‐receptor affinity ( K i = 3.3 μM) 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 μ‐ ( K i = 16.0 μM), κ‐ ( K i = 2.8 μM), and σ‐receptors ( K i = 14.5/1.26 μM). The biphasic competition curves obtained during σ‐receptor binding studies of 19d and 26 (two Ki values) may be explained by different interaction with σ‐receptor subtypes.