title: Search for the pharmacophore in kappa-agonistic diazabicyclo[3.3.1]nonan-9-one-1,5-diesters and arylacetamides.
abstract: Several heterocyclic bicyclo[3.3.1]nonan-9-ones were found to have a high affinity to kappa opioid receptors, 3,7-Diazabicyclononanones with 2,4-dipyridyl side chains were the most potent agonists whereas the corresponding 3-oxa-7-azabicyclo[3.3.1]nonan-9-one and compounds with phenyl substituents in 2 and 4 position are almost inactive. The purpose of this study was to unravel the active conformation of the bicyclononanones using well-known kappa-selective agonists such as ketocyclazocine, arylacetamides, several isoquinolines, CI-977, and four stereoisomers of EMD-61753 for comparison. In order to determine the geometry of the diazabicycles in solution pH-dependent NMR measurements of the bicycles were recorded and the results were related to the geometries of the aforementioned kappa agonists obtained from semiempirical PM3 calculations. A chair-boat conformation and a protonation at the N7 nitrogen atom of the diazabicyclononanones were found to be the pharmacophoric conformation. Comparison of the spatial arrangements, electrostatic, hydrophobic, and hydrogen bonding potentials of all kappa-selective agonists led to a model of structure-activity relationships of ligands of the kappa receptor. The arrangement of the pharmacophoric elements is characterized by an almost parallel orientation of a carbonyl and a protonated NH function in conjunction with at least one aromatic ring. Ketocyclazocine is only able to adopt this parallel orientation when the nitrogen is inverted relative to the X-ray structure. Furthermore, two binding sites for the aromatic rings are discussed. The pharmacological results of all considered bicyclononanone derivatives as well as of the four enantiomers of EMD-61753 can be understood and consistently explained in this way.
authors.affiliation: Pharmazeutisches Institut, Universität Bonn, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Brandt
authors.forename: S
authors.initials: S
authors.lastname: Drosihn
authors.forename: M
authors.initials: M
authors.lastname: Haurand
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: C
authors.initials: C
authors.lastname: Nachtsheim
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009294:Narcotics / Q000819:agonists; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000577:Amides; D001643:Bridged Bicyclo Compounds; D004952:Esters; D006571:Heterocyclic Compounds; D009294:Narcotics; D011725:Pyridines; D011957:Receptors, Opioid