Conformationally constrained kappa receptor agonists: stereoselective synthesis and pharmacological evaluation of 6,8-diazabicyclo[3.2.2]nonane derivatives.
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: CO(2)CH(3) > benzyl > COCH(2)CH(3). Bicyclic derivatives with (1S,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 kappa 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 [(35)S]GTPgammaS-binding assay at human kappa-opioid receptors, ent-23 was proved to be a full agonist with the same EC(50) value (87 nM) as the prototypical full agonist U-69,593 (EC(50) = 80 nM).
Geiger
Christian
C
Institut für Pharmazeutische und Medizinische Chemie der Westfalischen, Wilhelms-Universität Münster, Münster, Germany.
Zelenka
Christel
C
Lehmkuhl
Kirstin
K
Schepmann
Dirk
D
Englberger
Werner
W
Wünsch
Bernhard
B
D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D053961:Azabicyclo Compounds; D017473:Receptors, Opioid, kappa; C550170:methyl 8-(2-(3,4-dichlorophenyl)acetyl)-2-(pyrrolidin-1-yl)-6,8-diazabicyclo(3.2.2)nonane-6-carboxylate