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Search for the Pharmacophore in Kappa‐agonistic Diazabicyclo[3.3.1]nonan‐9‐one‐1,5‐diesters and Arylacetamides
Author(s) -
Brandt Wolfgang,
Drosihn Susanne,
Haurand Michael,
Holzgrabe Ulrike,
Nachtsheim Corina
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290607
Subject(s) - chemistry , pharmacophore , protonation , stereochemistry , ring (chemistry) , hydrogen bond , aromaticity , bicyclic molecule , ligand (biochemistry) , molecule , receptor , organic chemistry , ion , biochemistry
Abstract Several heterocyclic bicyclo[3.3.1]nonan‐9‐ones were found to have a high affinity to k 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 k‐selective agonists such as ketocyclacocine, 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 k agonists obtained from semiempirical PM3 calculations. A chair‐boat conformation and a protonation at the N 7 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 k‐selective agonists led to a model of structure‐activity relationships of ligands of the k‐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.