Stereoselective synthesis and structure-affinity relationships of bicyclic kappa receptor agonists.
Reductive amination of the bicyclic ketone 4 led diastereoselectively to endo-configured amines, which were transformed into the amides 7-10. The synthesis of the diastereomers 25 with an exo-configured amino moiety at position 6 was only successful after deactivation of both N-atoms of the 1,4-diazabicyclo[3.3.1]nonane system. The N-1-oxide 19 with an N-4-tosyl moiety was the crucial intermediate, which allows SN2 substitution with NaN3 under inversion of the configuration at position 6. Whereas the endo-configured pyrrolidine 7a (WMS-1302) revealed a kappa receptor affinity of 73 nM, the exo-configured diastereomer 25a was almost inactive at the kappa receptor (Ki > 1 microM). Replacement of the 3,4-dichlorophenylacetyl residue by other acyl and sulfonyl residues showed that it is essential for high kappa affinity. The kappa receptor affinities of the conformationally constrained pyrrolidines 7a and 25a were correlated with the dihedral angle N(pyrrolidine)-C-C-N(acetamide). A systematic conformational analysis of the potent but flexible kappa agonist 2 showed that a dihedral angle of 168 degrees (as in 25a) is energetically more disfavored than a dihedral angle of 58 degrees (7a). However, even the conformation with a dihedral angle of 58 degrees does not represent an energy minimum, which might explain the reduced kappa affinity of 7a.
Kracht
Daniel
D
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Rack
Elisabeth
E
Schepmann
Dirk
D
Fröhlich
Roland
R
Wünsch
Bernhard
B
D000818:Animals; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C032519:pyrrolidine