Synthesis and opioid receptor affinity of a series of 2,4-diaryl-substituted 3,7-diazabicylononanones

3,7-Diazabicyclo[3.3.1]nonan-9-ones having aryl rings in positions 2 and 4 with systematically varied substituents were synthesized using a double Man nich procedure. Radioligand binding assays were performed to measure the af finity of the compounds to the mu-, delta-, and kappa-opioid receptors. The affinity of all 2,4-diphenyl-substituted 3,7-diazabicyclo[3.3.1]nonan-9-on es to the mu- and delta-receptors was found to be low. In contrast, with ex ception of the nitro- and cyanophenyl-substituted compounds, most of the di azabicycles showed considerable affinity for the kappa-receptor. In particu lar, the m-fluoro-, p-methoxy-, and m-hydroxy-substituted compounds have an affinity in the submicromolar range. Due to solubility problems in aqueous media, salts of HZ2 were synthesized. The methiodide shows high kappa-affi nity and may, thus, be a promising candidate for development of a periphera l kappa-agonist, e.g. for use in the case of rheumatoid arthritis.