Kappa-receptor selective binding of opioid ligands with a heterocyclic bicyclo[3.3.1]nonan-9-one structure

Benyhe, S. and Márki, Á. and Nachtsheim, Corina and Holzgrabe, Ulrike and Borsodi, Anna (2003) Kappa-receptor selective binding of opioid ligands with a heterocyclic bicyclo[3.3.1]nonan-9-one structure. Acta Biologica Hungarica, 54 (2). pp. 147-155. ISSN 0236-5383

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Abstract

Previous pharmacological results have suggested that members of the heterocyclic bicyclo[3.3.1]nonan- 9-one-like compounds are potent κ-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 κ1 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 κ-selective benzomorphan compound; when compared to the arylacetamide structure of U-69,593, a specific κ1-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.

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