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Dagmar Hönack - One of the best experts on this subject based on the ideXlab platform.
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effects of the non nmda antagonists nbqx and the 2 3 Benzodiazepine gyki 52466 on different seizure types in mice comparison with diazepam and interactions with flumazenil
British Journal of Pharmacology, 1994Co-Authors: Wolfgang Loscher, Dagmar HönackAbstract:1 GYKI 52466 is a Benzodiazepine Derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated Benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 Benzodiazepine Derivative GYKI 52466 and 1,4-Benzodiazepines such as diazepam, the Benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the Benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2 Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10–20 mg kg−1), NBQX (80–120 mg kg−1) and diazepam (5 mg kg−1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing the myoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect. 3 With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment. 4 Flumazenil (5–20 mg kg−1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test. 5 The data indicate that the GABAA receptor-associated Benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment, thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
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Effects of the non‐NMDA antagonists NBQX and the 2,3‐Benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil
British journal of pharmacology, 1994Co-Authors: Wolfgang Loscher, Dagmar HönackAbstract:1 GYKI 52466 is a Benzodiazepine Derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated Benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 Benzodiazepine Derivative GYKI 52466 and 1,4-Benzodiazepines such as diazepam, the Benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the Benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2 Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10–20 mg kg−1), NBQX (80–120 mg kg−1) and diazepam (5 mg kg−1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing the myoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect. 3 With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment. 4 Flumazenil (5–20 mg kg−1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test. 5 The data indicate that the GABAA receptor-associated Benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment, thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
Wolfgang Loscher - One of the best experts on this subject based on the ideXlab platform.
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effects of the non nmda antagonists nbqx and the 2 3 Benzodiazepine gyki 52466 on different seizure types in mice comparison with diazepam and interactions with flumazenil
British Journal of Pharmacology, 1994Co-Authors: Wolfgang Loscher, Dagmar HönackAbstract:1 GYKI 52466 is a Benzodiazepine Derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated Benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 Benzodiazepine Derivative GYKI 52466 and 1,4-Benzodiazepines such as diazepam, the Benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the Benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2 Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10–20 mg kg−1), NBQX (80–120 mg kg−1) and diazepam (5 mg kg−1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing the myoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect. 3 With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment. 4 Flumazenil (5–20 mg kg−1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test. 5 The data indicate that the GABAA receptor-associated Benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment, thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
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Effects of the non‐NMDA antagonists NBQX and the 2,3‐Benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil
British journal of pharmacology, 1994Co-Authors: Wolfgang Loscher, Dagmar HönackAbstract:1 GYKI 52466 is a Benzodiazepine Derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated Benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 Benzodiazepine Derivative GYKI 52466 and 1,4-Benzodiazepines such as diazepam, the Benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the Benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2 Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10–20 mg kg−1), NBQX (80–120 mg kg−1) and diazepam (5 mg kg−1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing the myoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect. 3 With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment. 4 Flumazenil (5–20 mg kg−1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test. 5 The data indicate that the GABAA receptor-associated Benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment, thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
Makoto Otsuki - One of the best experts on this subject based on the ideXlab platform.
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Effects of a new Benzodiazepine Derivative cholecystokinin receptor antagonist FK480 on pancreatic exocrine secretion in anesthetized rats
Digestive Diseases and Sciences, 1994Co-Authors: Issei Tachibana, Makoto OtsukiAbstract:Inhibitory effects of a newly developed Benzodiazepine Derivative (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk][1,4] Benzodiazepine-3yl]-1H-indole-2-carboxamide (FK480), a cholecystokinin (CCK) -A receptor antagonist, on pancreatic exocrine secretion were examinedin vivo in anesthetized rats. The antagonism produced by FK480 was competitive in nature because intraduodenal as well as intravenous infusion of FK480 (50–250 nmol/kg/hr) caused a parallel rightward shift of the entire dose-response curve for cerulein-stimulated pancreatic exocrine secretion without altering the maximal increase. The magnitude of the shift was proportional to the dose of FK480. The mean pA2 and ID50 values of intravenously administered FK480 were 8.2 and 24 nmol/kg/hr, respectively, and those of intraduodenally infused FK480 were 7.7 and 168 nmol/kg/hr, respectively. Thus, FK480 given by the intravenous route was about sevenfold more potent than that given by the oral route. The antagonistic effects produced by intravenous FK480 were specific for CCK receptor in that the stimulatory effects of cerulein were inhibited whereas those of bombesin and secretin were not altered. In addition, intravenous administration of 50 nmol/kg/hr FK480 completely suppressed pancreatic exocrine secretion in response to intraduodenal infusion of 10% casein (400 mg/hr). FK480 was active as a CCK receptor antagonist for more than 12 hr because oral administration of FK480 (1.0 mg/kg) had significant inhibitory effects even after 12 hr on cerulein-stimulated pancreatic exocrine secretion. These results indicate that FK480 is a potent, competitive, and specific CCK receptor antagonist on the exocrine pancreasin vivo, having oral bioavailability and a long biological half-life.
Takefumi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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effects of discontinuing Benzodiazepine Derivative hypnotics on postural sway and cognitive functions in the elderly
International Journal of Geriatric Psychiatry, 2010Co-Authors: Kenichi Tsunoda, Hiroyuki Uchida, Takefumi Suzuki, Koichiro Watanabe, Tetsumori Yamashima, Haruo KashimaAbstract:Objective Benzodiazepines (BZDs) have been reported to cause negative impacts on body stability and cognitive functions, which in turn could result in lethal incidents, including falls, especially in the elderly. This fact notwithstanding, no systematic trial has evaluated the feasibility and benefits of discontinuing BZD-Derivative hypnotics in this population, which was addressed in this study. Methods In this 8-week open-label study, subjects aged ≥60 living in a nursing home who received BZD as a hypnotic were recruited. The BZD dose was tapered off over 3 weeks. The following assessments were performed 12 h post-dose at baseline and at endpoint: the Clinical Stabilometric Platform (CSP), the Critical Flicker Fusion Test (CFF), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Leeds Sleep Evaluation Questionnaire (LSEQ). Results Thirty subjects were enrolled (mean ± SD age = 79.1 ± 8.9 years, mean ± SD flurazepam equivalent BZD dose = 19.5 ± 10.9 mg/day). Psychiatric diagnoses (DSM-IV) of subjects were as follows: schizophrenia (n = 12), primary insomnia (n = 9), dementia (n = 7), and bipolar disorder (n = 2). In 26 completers, significant changes were found in a total length and a range of trunk motion with eyes closed. Significant improvements were also observed in the CFF and RBANS immediate memory, language, and attention index scores. Subjective worsening in sleep was not reported in those completers, assessed with the LSEQ. Conclusions Our results suggest that discontinuation of BZD hypnotics is feasible in a majority of elderly persons and leads to an improvement in the stability of body and a recovery in cognitive functions during the daytime. Copyright © 2010 John Wiley & Sons, Ltd.
Guisen Zhang - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and biological evaluation of novel cns 7056 Derivatives as sedatives in rats and rabbits
Chemical Biology & Drug Design, 2016Co-Authors: Yan Liu, Jianyong Xie, Tao Wang, Guisen ZhangAbstract:A new water-soluble Benzodiazepine Derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast-onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 Derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL-001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL-001 was chosen as the optimal compound for studies of ED50 , LD50 , latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL-001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL-001 has a shorter period of induction despite a slightly longer sedative duration and recovery time.