Kappa-receptor selective binding of opioid ligands with a heterocyclic bicyclo[3.3.1]nonan-9-one structure.
Previous pharmacological results have suggested that members of the heterocyclic bicyclo[3.3.1]nonan-9-one-like compounds are potent kappa-opioid receptor specific agonists. One lead molecule of this series. called compound 1 (dimethyl 7-methyl-2,4-di-2-pyridyl-3.7-diazabicyclo[3.3.1]nonan-9-one-1,5-dicarboxylate) exhibited high affinity for [3H]ethylketocyclazocine and [3H]U-69.593 binding sites in guinea pig cerebellar membranes which known to be a good source for kappa1 receptors. It was shown by molecular modelling that heterocyclic bicyclo[3.3.1]nonan-9-ones fit very well with the structure of ketazocine, a prototypic kappa-selective benzomorphan compound; when compared to the arylacetamide structure of U-69.593, a specific kappa1-receptor agonist, a similar geometry was found with a slightly different distribution of the charges. It is postulated, that the essential structural skeleton involved in the opioid activity is an aryl-propyl-amine element distributed along the N7-C6-C5-C4-aryl bonds.
Benyhe
S
S
Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, P.O. Box 521, H-6701 Szeged, Hungary. benyhe@nucleus.szbk.u-szeged.hu
Márki
A
A
Nachtsheim
Corina
C
Holzgrabe
Ulrike
U
Borsodi
Anna
A
D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D002531:Cerebellum / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D008024:Ligands; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C458301:bicyclo(3.3.1)nonane