1228313-58-3Relevant academic research and scientific papers
Conformationally constrained κ receptor agonists: Stereoselective synthesis and pharmacological evaluation of 6,8-diazabicyclo[3.2.2]nonane Derivatives
Geiger, Christian,Zelenka, Christel,Lehmkuhl, Kirstin,Schepmann, Dirk,Englberger, Werner,Wünsch, Bernhard
supporting information; experimental part, p. 4212 - 4222 (2010/08/22)
Three sets of stereoisomeric bicyclic κ 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 κ affinity decreased in the following order depending on the N-substituent: CO2CH3 > benzyl > COCH 2CH3. Bicyclic derivatives with (1S,2R,5R)-configuration showed the highest κ receptor affinity, which led to dihedral angles of 97° and 45° for the N(pyrrolidine)-C-C-N(phenylacetamide) structural element. The most potent κ 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 K i value of 1.0 nM. ent-23 revealed high selectivity against the other classical opioid receptors and related receptor systems. In the [ 35S]GTPγS-binding assay at human κ-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).
