Quinazolines and 1,4-Benzodiazepines. XXV.<sup>1</sup> Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones

Sternbach, L. H.; Archer, G. A.; Earley, J. V.; Fryer, R. Ian; Reeder, E.; Wasyliw, N.; Randall, Lowell O.; Banziger, R

doi:10.1021/jm00330a019

Cited by 35 publications

(10 citation statements)

References 2 publications

(2 reference statements)

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“…Sternbach et al [18] reported that variation of the substituents at position 7 does not have a consistent effect on potency from the findings that similar effects were found for 7-chloro-, 7-bromo-, 7-trifluoromethyl-, or 7-nitro-substituted compounds on anti-pentetrazol activity. On the contrary, Loew et al [17] described that 1,4-benzodiazepines with a nitro group at position 7 had a more potent anticonvulsant activity than the compounds having a chloro group at the same position.…”

Section: Discussionmentioning

confidence: 95%

“…Sternbach et al [18] also described in a mouse antipentetrazol test that compounds having a fluoro group at position 2) were generally more potent than those having a hydrogen or chloro group at the same position. As shown in the present study, however, introduction of a fluoro or chloro group was ineffective in causing a high anticonvulsant activity in amygdaloid-kindled seizures (diazepam vs.…”

Section: Discussionmentioning

confidence: 99%

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Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Fukinaga¹,

Ishizawa²,

Kamei³

1998

Pharmacology

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The effects of 14 different 1,4-benzodiazepines on amygdaloid-kindled seizures and their chemical structure-related anticonvulsive actions were studied. The prophylactic effects of 1,4-benzodiazepines on amygdaloid-kindled seizures were also examined. Male Wistar strain rats were used in this study. Rats were anesthetized with pentobarbital sodium (35 mg/kg i.p.) and bipolar electrodes were implanted into the right amygdala. The stimulating parameters were 1 ms pulse duration, 60 Hz frequency and a 1 s duration at an intensity just sufficient to induce afterdischarge (AD). All the 1,4-benzodiazepines depressed both seizure stage and AD duration of amygdaloid-kindled seizures. Of the 1,4-benzodiazepines, prazepam, flutoprazepam and flurazepam with a long alkyl chain at position 1 were less effective than the drugs having a hydrogen or methyl group at the same position. Nitrazepam, nimetazepam, flunitrazepam and clonazepam which have a nitro group at position 7 showed more potent antiepileptic activity than the drugs with a chloro group. Certain 1,4-benzodiazepines caused inhibition of the development of amygdaloid-kindled seizures. The existence of a hydrogen or methyl group at position 1 and a nitro group at position 7 is important for exhibiting potent anticonvulsant activity in amygdaloid-kindled seizures. Introduction of an oxygen group at position 2 is also necessary for high activity. 1,4-benzodiazepines had not only therapeutic but also prophylactic effects on amygdaloid-kindled seizures.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Fukinaga¹,

Ishizawa²,

Kamei³

1998

Pharmacology

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“…R1 in (1) R2 in ( 1 ) Flurazepam ( the simultaneous analysis of unchanged fluorazepam and its metabolites. Procedures using the combination of GC and negative ion chemical ionization MS [13] were the most specific and sensitive, especially for flurazepam, but routine determinations could not be performed with this method.…”

Section: Compoundmentioning

confidence: 99%

Determination of flurazepam and its hydroxyethyl and dealkyl metabolites by some packed and capillary ECD‐GLC methods: Application to pharmacokinetic studies

Coassolo

Aubert

Cano

1984

J. High Resol. Chromatogr.

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SummaryA sensitivegas-liquid chromatographicassay was developedfor plasma determinations of flurazepam (F), N1 -desalkylflurazepam (DF), and Nl-hydroxyethylflurazepam (HF). The internal standards used were delorazepam for F and DF and 1 a-hydroxymidazolam for HF. Following extraction and derivatization for HF, these compounds were analyzed by ECD-GLC, using either glass packed columns (poly A 103 for F and DF, OV 225 for HF) or CP-SiI 5 capillary columns for DF and HF. The detection limit of the packed-column assay was approximately 3 ng/ml for HFand DF, and 5 ng/ml for F; with capillary GLC analysis, the sensitivity limit for HF and DF was lower than 1 ng/mbThese methods were used for pharmacokinetic investigations after i.v. administration of these compounds.

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“…After oral administration, no flurazepam was detected in the urine; the major metabolite was V, while lesser amounts of conjugated IV and free I-DE were excreted. At 5 min., the (1 The urinary excretion of metabolites in 36 hr. In addition, the excretion of small amounts of intact drug (0.2% of the dose), Compound I, and conjugated I1 was seen only after intravenous drug administration.…”

Section: Metabolism In the Dog-excretion Of Labeled Drug And Metab-mentioning

confidence: 99%

“…The synthesis (1) and the pharmacology (2) of flurazepam hydrochloride, 7-chloro-1 -(2-diethylaminoethyl)-5-(2-fluorophenyl)-l,3-dihydro-2H-1,4-benzodiazepin-2one dihydrochloride, have been reported as well as the clinical use of this compound (also designated Ro 5-6901) as a hypnotic (3,4).…”

mentioning

confidence: 99%

Metabolism of Flurazepam, a Benzodiazepine, in Man and Dog

Schwartz

Postma

1970

Journal of Pharmaceutical Sciences

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Quinazolines and 1,4-Benzodiazepines. XXV.¹ Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones

Cited by 35 publications

References 2 publications

Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Determination of flurazepam and its hydroxyethyl and dealkyl metabolites by some packed and capillary ECD‐GLC methods: Application to pharmacokinetic studies

Metabolism of Flurazepam, a Benzodiazepine, in Man and Dog

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Quinazolines and 1,4-Benzodiazepines. XXV.1 Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones

Cited by 35 publications

References 2 publications

Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and Their Chemical Structure-Related Anticonvulsant Action

Determination of flurazepam and its hydroxyethyl and dealkyl metabolites by some packed and capillary ECD‐GLC methods: Application to pharmacokinetic studies

Metabolism of Flurazepam, a Benzodiazepine, in Man and Dog

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Quinazolines and 1,4-Benzodiazepines. XXV.¹ Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones