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J Knabe

Publications and source records attributed to J Knabe.

At least 19 recordsLinked to original sources
PubMed1997

[Racemates and enantiomers of basic, substituted 5-phenylhydantoins, synthesis and anti-arrhythmic action].

The racemates and the enantiomers of 5-phenylhydantoins with basic substituents in 5-position are synthesized on two different routes via the Bucherer-Bergs-reaction. Using lanthanide-shift-reagents the enantiomeric excess for the enantiomers of 3-methyl-5-morpholinomethyl-5-phenylhydantoin (3a) and 3-methyl-5-phenyl-5-(2-phthalimidoethyl)-hydantoin (6a) is found to be more than 98%. The enantiomers of 4d, 5b, 6b, 7a, and 7b, derived from 3a and 6a, possess the same optical purity. The racemates and the enantiomers of 3a, 4d and 5b were tested at atrium of rat hearts on their antiarrhythmic activity. At the right atrium (+)-3a, (+)-4d, and (+)-5b reduce the spontaneous frequence dependent on the dosis. At the left atrium the enantiomers of 3a and 4d show a negative inotropic action (+)-3a is 4.1, (+)-4d is 1.5 more active as the corresponding (-)-enantiomers. Compound (+)-4d exceeds the reference substance diphenylhydantoin by the factor 1.3.

Animals↗
PubMed1995

[1,5-Benzodiazepines. 2. Diametrically opposite central nervous system actions of the two stereoisomers of 3,3-dialkyl-1,5-benzodiazepine-2,4-diones].

I.p. applicated S(+)-1, R(-)-1 und rac. 1 prolonged hexobarbital sleeping in rats. The rac. 8-chloro compound 3 given i.p. produced no prolongation. Determination of rac. 1 in serum and tissues of rats 30 min after i.p. administration of 50 mg/kg showed that rac. 1 was detectable in serum and brain, yet its concentration was below the limit of determination. I.v. applicated, the enantiomers of 1 and 3 showed diametrically opposite CNS-effects: The S(+)-enantiomers were convulsively active as pentetrazol, whereas the R(-)-enantiomers were CNS depressant active prolonging hexobarbital sleeping time dose-dependently. High doses of diazepam antagonized dose-dependently the convulsive action of S(+)-1 supporting the hypothesis that this enantiomer acted as a strong inverse agonist, whereas R(-)-1 produced weak agonistic activity at the benzodiazepine binding site of the GABA-receptor.--Enantioselective differences for the binding of the 1-enantiomers to human serum albumin were found, too. R(-)-1 was bound to a greater extent than S(+)-1.

Animals↗
PubMed1995

Influence of albumin concentration, albumin species, pH and temperature on the stereoselectively different binding of (S)-(+)- and (R)-(-)-1-methyl-5-phenyl-5-propyl-barbiturate to serum albumin.

Using normal conditions (phosphate buffer pH 7.4, room temperature) and 1% human serum albumin (HSA), (R)-(-)-1-methyl-5-phenyl-5-propyl-barbiturate = (R)-(-)-1) as compared to (S)-(+)-1 was preferentially bound to albumin: the difference in the enantioselective binding was large (factor of 2) with low substrate concentrations and much smaller (factor of 1.3) with high substrate concentrations (range 5-620 micrograms/ml); with (S)-(+)-1 the decrease of the percent binding values observed with increasing concentrations was only moderately marked. The stereoselective binding difference ((R)-(-)- being greater than (S)-(+)-1) was always present independent of the albumin concentration (range 0.5-10%), the pH value (range 5-10) and the temperature (range 5-50 degrees C). Using 20 micrograms/ml as substrate concentration the stereospecific binding difference was large in solutions with low HSA concentration, in acidic and neutral pH range, and in experiments with low temperature. In contrast to HSA, bovine as well as rabbit serum albumin bound (S)-(+)-1 to a higher percentage than (R)-(-)-1; using rat serum albumin an enantioselective binding difference was not obtained. Taking into account for each of three mammalian albumins the respective number of binding classes and sites in each class, the affinity constant and total binding constant, it becomes evident that they bind (S)-(+)- and (R)-(-)-1 quantitatively differently in a species-specific manner.

Animals↗
PubMed1993

[Cyclic ureas. 1. Racemates and enantiomers of hexahydropyrimidine-2-ones: synthesis, configuration and sedative-hypnotic action].

The racemates and the enantiomers of the hexahydropyrimidin-2-ones 2a-2e which can be regarded as cyclic ureas are obtained from the racemates and the enantiomers of the barbiturates 1a-1e by reduction with LiAlH4/AlCl3. The enantiomers of 2a-2d, dextrorotatory in ethanol, possess S-configuration. In a study with rats all cyclic ureas synthesized showed sedative-hypnotic activity. Some of the enantiomers exhibited marked enantioselecive differences in their potency.

Animals↗
PubMed1993

[Cyclic ureas. 2. Racemates and enantiomers of imidazolidin-2-ones: synthesis, configuration and sedative-hypnotic action].

The racemates and the enantiomers of the imidazolidin-2-ones 2a and 2b, which can be considered as cyclic ureas, are obtained from the racemates and the enantiomers of the hydantoins 1a and 1b by reduction with LiAlH4/AlCl3. The enantiomers that are dextrorotating in ethanol possess S-configuration. In a study with Wistar-rats, 2a and 2b show sedative-hypnotic activity. The enantiomers exhibit marked enantioselective differences in their potency.

Animals↗
PubMed1993

Cyclic ureas, III: On the metabolism of the enantiomers of cyclic ureas in rats.

Studies are described on the metabolism of the enantiomers of 1, 2, and 3 in rats. The metabolites were identified in urine after cleavage of conjugates and extraction using gas chromatography-mass spectrometry. Qualitative enantioselective differences of the metabolism of 1, 2, and 3 could not be detected. Because oxidation of 1 and 2 to the corresponding barbiturates could not be found and 3 was oxidized to mephenytoin only in minor amounts, this pathway is not a prerequisite for the sedative-hypnotic effects of 1, 2, and 3.

Animals↗
PubMed1990

[Stereoselective differences of central nervous system-depressive action of a homologous series of 3-alkyl-thalidomide analysis].

The racemates and the enantiomers of the 3-alkyl-thalidomide analogues 2a-c were synthesized via the lactams 1a-c. The absolute configuration of 1a-c and 2a-c was elucidated, their enantiomeric purity established. From racem. 2a 1,3-dimethylthalidomide (3) was synthesized. By means of the hexobarbital sleeping time prolongating effect in rats it was shown that racem. 2a and 3 were less CNS-depressant active than thalidomide; 3 caused a more prolonged sleeping time than 2a. Both enantiomers of 2a (i.p. 200 mg/kg) exceeded in their sleeping time prolongation action racem. 2a (same dose), whereby the (S)-enantiomer was to a factor of 1.8 more effective than the (R). With both enantiomers of 2a time and dose dependency of the effect were investigated. The enantiomers of 2b + c and 1a-c had also a prolongating effect on the hexobarbital sleeping time. Independently of the alkyl group the (S)-enantiomers were always more active than the respective (R)-enantiomers. (S)-1b (200 mg/kg) caused a long lasting loss of the righting reflexes as "own effect". Stereoselective differences between the enantiomers of 2a and 2b were observed only when a dose of 200 mg/kg was applied, whereas the higher activity of the (S)-enantiomers of 2c, 1b + c was obtained already with a lower dosage range.

Animals↗
PubMed1989

[The enantioselectivity of drugs].

The syntheses of racemic and enantiometric basically substituted barbiturates, pyrrolidinediones (succinimides) and piperidinediones (glutarimides) are reported. Their absolute configurations are determined. In animal experiments most of the enantiomers show differences in their efficiency. The enantiomers of the barbiturates 4b and 4h and of the pyrrolidinedione 23a possess qualitatively different effects: (S) (-) 4b and (R) (+) 4h are narcotics, (R) (+) 4b and (S) (-)4h are convulsives; (R) (+) 23a is active as an anticonvulsant, (S) (-) 23a is toxic in the doses used.

Barbiturates↗