Synthesis and Opioid Receptor Affinity of a Series of 2,4-Diaryl-Substituted 3,7-Diazabicylononanones

Abstract

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 Mannich procedure. Radioligand binding assays were performed to measure the affinity 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-ones to the mu- and delta-receptors was found to be low. In contrast, with exception of the nitro- and cyanophenyl-substituted compounds, most of the diazabicycles showed considerable affinity for the kappa-receptor. In particular, 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-affinity and may, thus, be a promising candidate for development of a peripheral kappa-agonist, e.g. for use in the case of rheumatoid arthritis.

Comparison of Pharmacological Activities of Three Distinct κ Ligands (Salvinorin A, TRK-820 and 3FLB) on κ Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo

“…(Fig. 1) is a fluorphenyl derivative of HZ2, which was synthesized based on the 3,7-diazabicyclo[3.3.1]nonan-9-one skeleton (Siener et al, 2000). HZ2 exhibited high affinity for the opioid receptor in rat brain membranes (Siener et al, 2000).…”

“…1) is a fluorphenyl derivative of HZ2, which was synthesized based on the 3,7-diazabicyclo[3.3.1]nonan-9-one skeleton (Siener et al, 2000). HZ2 exhibited high affinity for the opioid receptor in rat brain membranes (Siener et al, 2000). HZ2 also showed a strong and long-lasting antinociceptive effect in the mouse tail-flick test (Kogel et al, 1998).…”

Stereochemistry and opioid receptor affinity of 2,4‐dipyridine‐3,7‐diazabicyclo[3.3.1]nonanones ‐ influence of the substituent in position N7

“…However, the 2-butyl and methylcyclohexyl substituted compounds 3 and 11 exhibit an unexpected high affinity to the κ-OR. Whereas in previous studies no µ-affinities have been found for any diazabicyclononanone [3,4,5,6] HZ2 and the corresponding alkyl substituted compounds 1 -5 show affinity for the human µ-OR in the micromolar range of concentration. Since compounds of mixed affinities to the µ and κ-OR such as buprenorphine and butorphanol are of increasing interest [12], the next step of pharmacological studies will be to work out whether the compounds are agonists or antagonists at either receptors and check the analgesic activity in animals.…”

“…All compounds synthesized were subjected to radioligand binding assays using [4,5,6]. Since the affinities measured in different assays are not directly comparable, for sake of comparison HZ2, its oxalate salt, bremazocine and U-50,488 were additionally measured.…”

Antibacterial Activity Exerted by some Diazabicyclo-steroid Derivatives Against Staphylococcus Aureus and Streptococcus Pneumoniae

“…There are several reagent for removal of silyl protecting groups from hydroxyl such as ammonium fluoride 45 , tris(dimethylamino)sulfonium /difluorotrimethyl silicate 46 , hydrofluoric acid 47 and others. In this study, hydrofluoric acid was used to removal of silyl-protecting group from hydroxyl of the compound 8 to form 9 (Scheme 5 Other results showed several signals of the 1 H NMR spectrum for 22at 0.88 and 0.98 ppm for methyl bound to steroid nucleus; at 1.68 ppm for methyl group bound to imino group; at 1.40, 1.90 and 2.06-2.10 ppm for methylene groups bound to both imino and cyclobutene ring; at 1.76, 2.12 and 2.42 ppm for methylene bound to both alkyne and imino groups; at 3.10-3.56 ppm for methylene groups bound to both imino and amino groups; at 4.24 ppm for both hydroxyl and amino groups; at 6.00 ppm for cyclobutene ring; at 7.70-8.10 ppm for imino groups.…”