Stereoselective synthesis and structure–affinity relationships of bicyclic κ 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 S_N2 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 (K_i > 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.