Showing papers by "Ulrike Holzgrabe published in 1996"

Conformational analysis, molecular shape comparison, and pharmacophore identification of different allosteric modulators of muscarinic receptors.

Abstract: Structurally dissimilar compounds such as alcuronium and the newly synthesized substances derived from the bisbenzyl ether TMB4 and from hexamethonium stabilize antagonist binding to M2-cholinoceptors which is indicative of an allosteric action. In order to propose a hypothesis for the common pharmacophore and the corresponding active conformations, seven flexible compounds in a data set were individually aligned onto the most active and, additionally, rigid alcuronium molecule using a torsional angle flexible fit. An S-shape conformation was found to be a plausible general active conformation. In a subsequent molecular shape analysis the overlap and the nonoverlap steric volumes, RMS alignment as well as electrostatic field potentials were employed as possible structure−activity correlation descriptors. The corresponding 3D-QSAR formulation exhibits a correlation between allosteric modulation potency and the nonoverlap steric volume as well as the proton and oxygen anion probe electrostatic field potenti...

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.

Syntheses and biological activities of new N1-aryl substituted quinolone antibacterials.

Abstract: A series of quinolones with a systematically varied substitution at the phenyl ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P, Rm) and the pKa values have been determined as well as the microbiological activity: The MIC values for eight different strains of three Gram-positive and three Gram-negative species and the inhibitory concentrations of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between antibacterial activity concerning the whole-cell system and electronic properties as well as the length of the substituents at the phenyl rings could be derived. The activity in a cell-free system was governed by the lipophilicity and the width of the substituents. It is speculated that the quinolones take a defined place in the DNA gyrase-DNA complex which is characterized by polar amino acids. This is in agreement with findings from studies of mutant gyrases.