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PubMed2003

Synthesis and anticonvulsant activity of some new dioxolane derivatives.

In this study, ten 2-acetylnaphthalene derivatives with a dioxolane structure were synthesized and screened for their anticonvulsant activities. Dioxolane derivatives were prepared by the reaction with appropriate ethanone, glycol and p-toluensulphonic acid. The structures of the compounds were elucidated by IR, 1H-NMR and elemental analysis. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES) test and subcutaneous metrazol (ScMet.) test. The rotarod toxicity test was used for the assessment of neurological deficits. According to the activity studies compound 6 was found neurotoxic, compounds, 1, 4, 5, 7-9 were found protective against MES and 7-10 were found protective against ScMet. Compounds 2 and 3 were found inactive.

Animals↗

PubMed2003

Design and synthesis of semicarbazones and their bio-isosteric analogues as potent anticonvulsants: the role of hydrogen bonding.

A series of p-nitrophenyl substituted semicarbazones (4a-c) and phenoxy/p-bromophenoxy acetyl hydrazones (8a-q) were synthesized and their anticonvulsant activity was screened against maximal electroshock seizure (MES), subcutaneous metrazole (ScMet) and subcutaneous strychnine (ScSty) tests. Compounds 4a-c with -NHCO- were found to be the most active in all these tests. These compounds were also active in the MES test after oral administration in rats. On the other hand, compounds 8a-q with -OCH2- were devoid of anticonvulsant activity. The studies revealed that the hydrogen bonding domain in semicarbazones, adjacent to the lipophilic aryl ring, is essential for the anticonvulsant activity.

Administration, Oral↗

PubMed2004

Anticonvulsant activity of Schiff bases of isatin derivatives.

Schiff bases of N-methyl and N-acetyl isatin derivatives with different aryl amines have been synthesized and screened for anticonvulsant activities against maximal electroshock (MES) and subcutaneous metrazole (ScMet). N-methyl-5-bromo-3-(p-chlorophenylimino) isatin (2) exhibited anticonvulsant activity in MES and ScMet with LD50 > 600 mg kg(-1), showing better activity than the standard drugs phenytoin, carbamazepine and valproic acid. Thus, compound 2 may be chosen as a prototype for development of new anticonvulsants.

Animals↗

PubMed1992

Synthesis and anticonvulsant activity of some new 4-aryl-4-imidazoline-2-one derivatives.

In this study, some new 4-aryl-4-imidazoline-2-one derivatives have been prepared by the reaction of potassium cyanate with some aminoethanone hydrochlorides. The structure of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (ScMet) tests according to the ADD (Antiepileptic Drug Development) programme Phase I. Neurotoxicity of the compounds was evaluated by rotarod test. While 2 of the compounds showed protection against ScMet induced seizures at 30 and 300 mg/kg dose levels, 3 of the compounds showed neurotoxicity.

Animals↗

PubMed2004

Synthesis of 4-aryl substituted semicarbazones of some terpenes as novel anticonvulsants.

PURPOSE: A series of 4-aryl substituted semicarbazones of citral and R- (-) carvone were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. METHODS: TLC evaluated purity of synthesized compounds and their structure confirmed by infrared spectroscopy, proton magnetic resonance spectroscopy and by nitrogen estimation. All the compounds were evaluated for anticonvulsant activity by maximal electroshock (MES) and subcutaneous metrazol (ScMet) induced seizure methods and minimal motor impairment was determined by rotorod test. RESULTS: All the synthesized compounds exhibited significant protection after intraperitoneal (i.p.) administration in MES. Seventy two percent of the compounds exhibited protection in ScMet test. Some of them also showed good activity after oral administration. The results showed that anticonvulsants with cyclic and acyclic terpenoid moiety retain activity in MES as well as ScMet test. The p-fluoro aryl substituted semicarbazones emerged as the most active analogue in both cyclic and acyclic terpenes. CONCLUSION: Semicarbazones with terpenoid as the lipophilic moiety resulted in compounds with broad spectrum of anticonvulsant activity and therefore, they may be utilized for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity. The results also validated pharmacophore model with four binding sites essential for anticonvulsant activity.

Acyclic Monoterpenes↗

PubMedDate not supplied

Synthesis and anticonvulsant properties of a series of N-substituted 2-aza-spiro[4.5]decane-1,3-diones and 8-phenyl-2-aza-spiro[4.5]decane-1,3-diones.

A series of N-phenyl-2-aza-spiro[4.5]decane-1,3-diones [III-VIIII] structurally related to the previously described N-phenyl-3-arylpyrrolidine-2,5-dione (11) was synthesized and tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc. MET) tests. The most potent of the series were N-(2-methylphenyl)-2-aza-spiro[4.5]decane-1,3-dione [III] and N-(3-methylphenyl)-2-aza-spiro [4.5]decane-1,3-dione [IV], which inhibited seizures in the MES and sc.MET tests. On the other hand, as a preliminary assay we synthesized and tested for the anticonvulsant activity a new N-substituted 8-phenyl-2-aza-spiro[4.5]decane-1,3-dione, containing either a benzyl or a cyclohexyl moiety [IX-XII] at the nitrogen atom. The obtained results showed that the presence and position of the methyl group in the aryl ring [III, IV], as well as an cyclohexane moiety [XI, XIII connected with the imide nitrogen atom, played the essential role for anticonvulsant activity.

Animals↗

PubMed2005

Synthesis and anticonvulsant activity of some new hexahydropyrimidine-2,4-dione derivatives.

In this study, twelve new hexahydropyrimidine-2,4-dione derivatives were synthesized and screened for their anticonvulsant activities. All the compounds (7a-1) which have 6-arylhexahydropyrimidine-2,4-dione and N,N-disubstituted dithiocarbamate structures were prepared by the reaction with appropriate 3-(2-chloroethyl)-6-arylhexahydropyrimidine-2,4diones and the corresponding N,N-disubstituted dithiocarbamate potassium salts. The structure of the synthesized compounds was confirmed by UV, IR, 1H-NMR and elemental analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous pentetrazol (metrazol, scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 6-(4-chlorophenyl)hexahydropyrimidine-2,4-dione derivatives (7e-h) were found to be highly protective against MES and scMet. Neurotoxicity was not observed in any of the tested compounds.

Animals↗

PubMed2005

Synthesis of and pharmacological studies on the antidepressant and anticonvulsant activities of some 1,3,5-trisubstituted pyrazolines.

Eighteen 1-phenyl-, 1-thiocarbamoyl- and 1-N-substitutedthiocarbamoyl-3-phenyl-5-heteroaryl-2-pyrazoline derivatives were synthesized and tested for their antidepressant and anticonvulsant activities. Their chemical structures were proved by spectral and microanalysis. The antidepressant activities of the compounds were investigated by the "forced swimming test". Results showed that compounds II-a, b, c, III-1b, 1c, 4a showed activities equivalent to or higher than pargyline hydrochloride (CAS 306-07-0) and tranylcypromine sulfate (CAS 13492-01-8) that were used as reference antidepressant drugs. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES), subcutaneous metrazol (ScMet.) and rotarod toxicity tests in mice according to the phase I tests of the Antiepileptic Drug Development programme. Compounds I-a, II-a, b, c, III-1b, 2a, 2c were found protective against MES and III-1b, 1c, 2a, 2c were found protective against ScMet.

Animals↗

PubMedDate not supplied

Synthesis and anticonvulsant activity of a series of N-substituted bicyclo [2.2.1] hept-5-ene-2,3-dicarboximides.

As part of our study, a series of N-phenyl- and N-benzyl-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximides [III-XVI], structurally related to the previously described N-phenyl- or N-pirydyl-3-arylpyrrolidine-2,5-dione [I, II], were synthesized and tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc. MET) tests. The most potent in the maximum electroshock seizure (MES) test were compounds with methyl [III] and chloro [XI] substituents at position -2 of the aromatic ring, whereas of all the synthesized compounds, only N-(2-methoxybenzyl)-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide [XII] was active in the sc. MET. Compounds with substituents at position -3 or -4 of the aromatic ring were found to be less active [V, VI, XIII and XIV], or devoid of activity [VII, IX, XV and XVI]. In contrast, the N-(4-chlorophenyl)-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide [VIII] at a dose of 100 mg/kg was active in the MES test.

Animals↗

PubMed1976

[Neuropsychiatric findings in a case of paramyoclonus multiplex].

In a subject affected with multiple paramyoclonus, showing asyncronous, bilateral, intermittent, spontaneous myoclonic jerks, a neuro-psychiatric investigation was performed. Several day-time poligraphic recordings were normal, while the night-time ones showed the lack of myoclonic jerks throughout the sleep. Metrazol activation pointed out a probable hyperexcitability of brain stem reticular formation. The psychiatric investigation, performed with a psychodynamic approach let realize the existence of a distortion of neuro-psychological functions due to an impaired elaboration of emotional information and psycho-structuring engrams. The Authors conclude for a posible convergence of biological and psychological factors causing the clinical symptoms.

Adult↗

PubMed1990

[Bombesin, dermorphin, physalaemin and sauvagine: effects on superficial and depth EEG tracings in epileptic and non-epileptic rats].

The effects of bombesin, sauvagine, physalaemin and dermorphin on rat CNS were observed. These peptides were administered to non-epileptic and epileptic rats: SEEG and DEEG were recorded. On the normal electrical background activity of rat brain only physalaemin had no effect. All the other peptides gave rise to slow activity with different duration. In the epileptic rat only sauvagine showed no effect whilst physalaemin reduced the epileptic activity, bombesin seemed to strengthen the action of metrazol and dermorphin blocked it at the onset. These observations will undergo FFT (Fast Fourier Transform) analysis.

Amphibian Proteins↗

PubMed1990

A novel potent non-benzodiazepine anxioselective agent with reduced dependence liability: ICI 198, 256.

ICI 198,256, a member of the cinnoline series, was shown to be a potent anxiolytic agent in several species of animals. In addition, ICI 198,256 exhibited potent activity as an antagonist of both metrazole and bicuculline-induced convulsions. The salient features of ICI 198,256 are that it possesses minimal sedative liability, lower ethanol interaction and possibly lower dependence liability than benzodiazepines (e.g., diazepam). Neurochemically, this structurally novel anxiolytic compound is potent and selective for the Type 1 (cerebellar) BZ receptors in vivo as well as ex vivo, and in addition shows an agonist BZ-like profile in a variety of systems. Thus, ICI 198,256 may offer several significant advantages in the treatment of anxiety in humans than existing benzodiazepines.

Animals↗

PubMed1990

Historical perspectives on anesthetic-related cardiac arrest and resuscitation.

Contemporary interest in resuscitation was historically related to anesthetic death. Primitive techniques of anesthetic administration, loss of airway control, and psychologically influenced sudden death contributed to unanticipated respiratory and cardiac arrest. Airway obstruction has remained the principal factor in asphyxial death, necessitating crucial preservation of respiratory function during induction of anesthesia. Early, disorganized overdose and arrest interventions included: application of cold water, manual artificial respiration, heat, friction and galvanic battery application. Cardiopulmonary resuscitation, after years of research and experimentation became an integrated plan of attack: mouth-to-mouth ventilation and maneuvers eliminating pharyngeal obstruction were proven effective; internal and external cardiac massage was incorporated and definitive drug therapy began with epinephrine, strychnine, caffeine, carbon dioxide, amyl nitrate, coramine, metrazol and procaine. Defibrillation proved electricity converted ventricular fibrillation to normal sinus rhythm. Significant lethality still occurs from anesthetic-induced cardiac arrest, despite technological advances. Causes of operating room cardiac arrests are numerous and include sudden death syndrome. Constant vigilance distinguishes variable patient response. Immediate recognition and coordinated intervention assures success.

Adolescent↗

PubMed1989

Antimetrazol action and plasma levels of valproate in developing rats.

The duration of protective action of valproate (VPA, 400 mg/kg i.p.) against metrazol-induced seizures was studied in rats aged 7, 12, 18 and 90 days. Fifteen, protected. The results differed between the various age groups after longer intervals: The protection was longest in 18-day-old rats--seizures did not appear even six hours after VPA administration. On the contrary, all 7-day-old rat pups exhibited seizures two hours after VPA. Plasma levels of VPA were measured by means of gas chromatography in the same age groups after an identical dose of VPA. After a single injection of VPA a clear-cut two-peak curve of plasma level was found in all young groups, which may be due to an enterohepatic recirculation of VPA. The maximum plasma levels were lowest in 7-day-old rats, the three older groups exhibited similar values. Plasma half-life was longest in the youngest animals (9.24) and decreased with age; values for 18- and 901 day-old rats did not differ (2.57 and 3.05 h respectively). No clear-cut correlation was found between the antimetrazol action and its plasma levels.

Aging↗

PubMed1989

Effects of the acute and chronic administration of chlordiazepoxide on the development of spontaneous motility in chick embryos.

The effects of the acute and chronic administration of chlordiazepoxide on spontaneous motility and on the reactivity of the generator of embryonic motility were studied in chick embryos from the 4th to the 19th day of incubation. 1. The acute administration of chlordiazepoxide (5 mg/kg e.w.) significantly depressed spontaneous motility from the 13th day of incubation. 2. The chronic administration of chlordiazepoxide (12.2 mg/kg e.w./24 h) from the 4th to the 8th, 12th and 16th day of incubation enhanced the reduction of the spontaneous motility of 17-day-old embryos. 3. The chronic administration of chlordiazepoxide significantly modified the activity of both activators (strychnine, metrazol, bicuculline, picrotoxin) and inhibitors (GABA, chlordiazepoxide) of the spontaneous motility of chick embryos.

Animals↗

PubMed1989

Are spontaneous activity and supraspinal control co-responsible for functional development of the generator of embryonic motility?

The effect of chronic administration of phenobarbital (from the 4th to the 16th day of incubation) combined with chronic spinal decentralization (decapitation at stage 11-13) on the development of spontaneous motor activity (recorded on the 17th day of incubation) was studied in 4 to 17-day-old chick embryos. 1. Combination of the two experimental treatments led to summation of their negative effect on development; spontaneous motor activity fell to 15.2% of the control value (to 26.9% after the isolated administration of phenobarbital and to 30.5% after isolated decapitation). 2. Metrazol activation of motor activity (100 mg/kg egg weight) after combination of the two factors was relatively no different from the results after their isolated use. 3. The acute administration of GABA (100 mg/kg e.w.) likewise induced relatively the same depression of spontaneous motility as after isolated chronic decapitation and the isolated chronic administration of phenobarbital. The results confirm the hypothesis of the significance of spontaneous activity of the spinal motoneurones for their survival and their actual functional development during the embryonic period.

Animals↗

PubMed1989

Pharmacological profile of the new anticonvulsant etazepine.

The pharmacological profile of the new anticonvulsant etazepine (5,6-dihydro-5-methyl-11H-11-ethoxy-dibenzo[b,e]azepin-6-one) was investigated. It protected mice and rats from a wide variety of convulsant agents (maximal electroshock, pentetrazol (metrazole), bicuculline, strychnine, 3-mercaptopropionic acid, nicotine, cefazoline and kainic acid) at doses about 16-45 times lower than those exerting neurotoxic effects (depending on the test used). The anticonvulsant effect of etazepine was long-acting (more than 24 h) and did not seem to develop tolerance. Moreover, etazepine did not prolong thiopental-induced sleeping time. Based on pharmacological studies etazepine seems to exert its anticonvulsant effects by activating the GABAergic system.

5-Hydroxytryptophan↗

PubMed1988

Consequences of chronic phenobarbital blockade of spontaneous motility in chick embryos for the development of central motor output activity.

The consequences of the chronic continuous administration of Na+-phenobarbital in an average dose of 9.8 mg/kg e.w./24 h were studied in chick embryos. Administration was always started on the 4th day of incubation and lasted 4-12 days. Spontaneous motility was tested in 13- and 17-day-old embryos. The continuous, chronic administration of phenobarbital produced the following significant changes in the embryos' spontaneous motor activity and in the reactivity of their central motor output: 1) In 17-day-old embryos it reduced spontaneous motility in direct correlation to the time of administration. In 13-day-old embryos the effect was not yet significant. 2) It significantly inhibited strychnine, bicuculline and metrazol activation of motor output. 3) It raised the sensitivity to the acute administration of oxazepam (by 18-29.4%), but weakened the inhibitory effect of gamma-aminobutyric acid (by 17.6-33.2%). From the results of these observations it is deduced that spontaneous central motor output activity is not just a developmental epiphenomenon, but that it is an important prerequisite for normal development of the embryonic CNS.

Animals↗