SEARCH FOR THE PHARMACOPHORE IN KAPPA-AGONISTIC DIAZABICYCLO[3.3.1]NONAN-9-ONE-1,5-DIESTERS AND ARYLACETAMIDES

Several heterocyclic bicylco[3.3.1]nonan-9-ones were found to have a h igh affinity to kappa opiod receptors. 3,7-Diazabicyclononanones with 2,4-dipyridyl side chains were the most potent agonists whereas the co rresponding 3-oxa-7-azabicyclo[3.3.1]nonan-9-one and compounds with ph enyl substituents in 2 and 4 position are almost inactive. The purpose of this study was to unravel the active conformation of the bicyclono nanones using well-known kappa-selective agonists such as ketocyclacon ine, arylacetamides, several isoquinolines, CI-977, and four stereoiso mers of EMD-61753 for comparison. In order to determine the geometry o f the diazabicycles in solution pH-dependent NMR measurements of the b icycles were recorded and the results were related to the geometries o f the aforementioned kappa agonists obtained from semiempirical PM3 ca lculations. A chair-boat conformation and a protonation at the N-7 nit rogen atom of the diazabicyclononanones were found to be the pharmacop horic conformation. Comparison of the spatial arrangements, electrosta tic, hydrophobic, and hydrogen bonding potentials of all kappa-selecti ve agonists led to a model of structure-activity relationships of liga nds of the kappa receptor. The arrangement of the pharmacophoric eleme nts is characterized by an almost parallel orientation of a carbonyl a nd protonated NH function in conjunction with at leat one aromatic rin g. Ketocyclazocine is only able to adopt this parallel orientation whe n the nitrogen is inverted related to the X-ray structure. Furthermore , two binding sites for the aromatic rings are discussed. The pharmaco logical results of all considered bicyclononanone derivatives as well as of the four enantiomers of EMD-61753 can be understood and consiste ntly explained in this way.