Conformationally Constrained kappa Receptor Agonists: Stereoselective Synthesis and Pharmacological Evaluation of 6,8-Diazabicyclo[3.2.2]nonane Derivatives

Geiger C, Zelenka C, Lehmkuhl K, Schepmann D, Englberger W, Wünsch B

Zusammenfassung

Three sets of stereoisomeric bicyclic kappa agonists with defined orientation of the pharmacophoric elements pyrrolidine and dichlorophenylacetamide were stereoselectively prepared and pharmacologically evaluated. Stereoselective reduction, reductive amination, and Mitsunobu inversions were the key steps for the establishment of the desired stereochemistry. The kappa affinity decreased in the following order depending on the N-substituent: CO2CH3 > benzyl > COCH2CH3. Bicyclic derivatives with (IS,2R, 5R)-configuration showed the highest kappa receptor affinity, which led to dihedral angles of 97 degrees and 45 degrees for the N(pyrrolidine)-C-C-N(phenylacetamide) structural element. The most potent K agonist of this series was (+)-methyl (1S,2R,5R)-8-[2-(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylate (ent-23, WMS-0121) with an kappa(i) value of 1.0 nM. ent-23 revealed high selectivity against the other classical opioid receptors and related receptor systems. In the [S-35]GTP gamma-S-binding assay at human kappa-opioid receptors, ent-23 was proved to be a full agonist with the same EC50 value (87 nM) as the prototypical full agonist U-69,593 (EC50 = 80 nM).