Issue 1, 2010
From the journal:

Organic & Biomolecular Chemistry

Stereoselective synthesis and structure–affinity relationships of bicyclic κ receptoragonists†

Daniel Kracht,a   Elisabeth Rack,a   Dirk Schepmann,a   Roland Fröhlichb  and  Bernhard Wünsch*a  

* Corresponding authors

a Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
E-mail: wuensch@uni-muenster.de
Fax: +49-251-8332144
Tel: +49-251-8333311

b Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, D-48149 Münster, Germany

Abstract

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 κ receptor affinity of 73 nM, the exo-configured diastereomer 25a was almost inactive at the κ receptor (Ki > 1 μM). Replacement of the 3,4-dichlorophenylacetyl residue by other acyl and sulfonyl residues showed that it is essential for high κ affinity. The κ 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 κ agonist 2 showed that a dihedral angle of 168° (as in 25a) is energetically more disfavored than a dihedral angle of 58° (7a). However, even the conformation with a dihedral angle of 58° does not represent an energy minimum, which might explain the reduced κ affinity of 7a.

Graphical abstract: Stereoselective synthesis and structure–affinity relationships of bicyclic κ receptor agonists

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Article information

DOI
https://doi.org/10.1039/B915180J
Article type
Paper
Submitted
27 Jul 2009
Accepted
30 Sep 2009
First published
12 Nov 2009

Org. Biomol. Chem., 2010,8, 212-225

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Stereoselective synthesis and structure–affinity relationships of bicyclic κ receptor agonists

D. Kracht, E. Rack, D. Schepmann, R. Fröhlich and B. Wünsch, Org. Biomol. Chem., 2010, 8, 212 DOI: 10.1039/B915180J

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