Chiral pool synthesis of enantiomerically pure morphan derivatives with κ receptor affinity from (S)-perillaldehyde

Ethylenediamines represent a promising class of κ receptor agonists. Recently, the first ethylenediamine - morphan hybrid 4 with high κ receptor affinity, but poor selectivity over the σ₁ receptor was reported. Herein, the chiral pool synthesis of substituted morphans 19 and 29 is reported combining the morphan scaffold with the κ-pharmacophoric elements dichlorophenylacetamide and pyrrolidine. Starting from methyl (S)-perillate (12), a two-step sequence, i.e., epoxidation followed by reaction with benzylamine, provided enantiomerically pure morphan-8-carboxylate 10a. Functional group modifications of the ester moiety and the benzylamine substructure of 10a led to the pyrrolidinomethyl derivative 19. Key step of the synthesis of pyrrolidine 29 was a Curtius rearrangement, in which the intermediate isocyanate was trapped with benzyl alcohol to obtain the carbamate 27. The κ affinity of pyrrolidine 29 (K_i(κ) = 138 nM) was approximately 7-8-fold lower than the κ affinity of morphan 4 without further substituents. However, taking lipophilicity into account resulted in almost identical LLE values for 4 (LLE = 5.66) and 29 (LLE = 5.56). The additional OH moiety of 29 not only increased the polarity, but also the receptor selectivity, as 29 did no longer interact with σ₁ receptors. Docking studies demonstrated similar binding poses of 4 and 29 at the κ receptor. Moreover, the reduced affinity of 29 towards κ and σ₁ receptors could be explained. In vitro,29 revealed high metabolic stability. Human peripheral blood mononuclear cells stimulated with lipopolysaccharide were used to show the anti-inflammatory and immunomodulatory effects of the κ receptor agonists 4 and 29.

Chiral pool synthesis; Computational studies; Curtius rearrangement; Ethylenediamine; Ligand-lipophilicity efficiency LLE; Morphan; Perillaldehyde; Selectivity; κ-opioid receptor affinity.