title: Mechanism of action of the diazabicyclononanone-type kappa-agonists.
abstract: The 2,4-di-2-pyridyl-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diester HZ2 was recently found to exhibit high affinity and selectivity to the kappa-opioid receptor (KOR) in combination with an unusually long duration of action. Docking of HZ2 to the putative binding site model of the KOR revealed HZ2 to be tightly sitting in the binding pocket. Strong interactions, especially salts bridges between the protonated nitrogens of HZ2 and the glutamic acids 209 and 297, nicely explain the high affinity of HZ2 to the KOR. A formation of a hemiaminal bond between the keto carbonyl group of HZ2 and a lysine residue (Lys200) may explain the long duration of action.
authors.affiliation: Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000737:chemistry*
chemical_list: C473673:3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridylbicyclo(3.3.1)nonane-1,5-dicarboxylic acid dimethyl diester; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D017473:Receptors, Opioid, kappa