title: 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.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Siener
authors.forename: A
authors.initials: A
authors.lastname: Cambareri
authors.forename: U
authors.initials: U
authors.lastname: Kuhl
authors.forename: W
authors.initials: W
authors.lastname: Englberger
authors.forename: M
authors.initials: M
authors.lastname: Haurand
authors.forename: B
authors.initials: B
authors.lastname: Kögel
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu