title: Diazabicyclononanones, a potent class of kappa opioid analgesics.
abstract: The 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Germany. holzgrab@pharmazie.uni-wuerzberg.de
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: A
authors.initials: A
authors.lastname: Cambareri
authors.forename: U
authors.initials: U
authors.lastname: Kuhl
authors.forename: T
authors.initials: T
authors.lastname: Siener
authors.forename: W
authors.initials: W
authors.lastname: Brandt
authors.forename: W
authors.initials: W
authors.lastname: Strassburger
authors.forename: E
authors.initials: E
authors.lastname: Friderichs
authors.forename: W
authors.initials: W
authors.lastname: Englberger
authors.forename: B
authors.initials: B
authors.lastname: Kögel
authors.forename: M
authors.initials: M
authors.lastname: Haurand
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D016314:Ethylketocyclazocine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: C471761:1,5-dimethyl-3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo(3.3.1)nonane-1,5-dicarboxylate; D000701:Analgesics, Opioid; D002264:Carboxylic Acids; D011725:Pyridines; D017473:Receptors, Opioid, kappa; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C012395:ketazocine