Pentylenetetrazole Induced Seizure Test Research Articles

Synthesis and anticonvulsant evaluation of N-Cbz-alpha-amino-N-alkoxysuccinimides.

In previous studies for the development of new anticonvulsants, we found that N-Cbz-alpha-amino-N-alkylsuccinimides exhibited significant anticonvulsant activities in the Maximal electroshock seizure (MES) and Pentylenetetrazole induced seizure (PTZ) tests, and also their anticonvulsant activities were dependent on the N-alkyl substituents existent in their structures. Based on these estimations, N-Cbz-alpha-amino-N-hydroxysuccinimide and various N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared in order to develop more active anticonvulsants and to examine the effects of N-hydoxy or N-alkoxy groups on their anticonvulsant activities. The (R)- or (S)-N-Cbz-alpha-amino-N-hydroxysuccinimide and N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared from the corresponding (R)- or (S)-N-Cbz-aspartic acid through the known synthetic procedures. Their anticonvulsant activities in the MES and PTZ test were evaluated. All of these compounds except 3a showed significant anticonvulsant activities against the PTZ test, but these compounds were not active in the MES test. The most active compound in the PTZ test was (R)-N-Cbz-alpha-amino-N-benzyloxysuccinimide (ED50=62.5 mg/kg). In addition, the anticonvulsant activities of these compounds were dependent on their N-substited groups. The order of anticonvulsant activity against the PTZ test, as judged from the ED50 values for (R) series was N-benzyloxy > N-hydroxy > N-isopropoxy > N-methoxy > N-ethoxy; for the (S) series N-ethoxy > N-benzyloxy > N-methoxy > N-isopropoxy.

Synthesis and anticonvulsant evaluations of N-cbz-alpha-amino-N-alkoxyglutarimides.

In our previous studies for the development of new anticonvulsant of broad spectrum, we found that N-cbz-alpha-aminoglutarimides showed significant anticonvulsant activities of broad spectrum enough to be recommended for the new anticonvulsants and their anticonvulsant activities were dependent on their imide substituent groups. Based on these results, various N-cbz-alpha-amino-N-alkoxyglutarimides, where the imide N-H was substituted with the hydroxy and alkoxy group, were prepared and evaluated for their anticonvulsant activities using the Maximal electroshock seizure (MES) and Pentylenetetrazole induced seizure (PTZ) tests and also the rotorod test. A series of (R) or (S)-N-cbz-alpha-amino-N-alkoxyglutarimides could be prepared from the corresponding (R) or (S)-N-cbz-glutamic acid following the usual synthetic procedure. Among them, (R)-N-cbz-alpha-amino-N-hydroxyglutarimide (ED50=86.25 mg/kg) was most active in the MES test. In the case of the PTZ test, (R)-N-cbz-alpha-amino-N-benzyloxyglutarimide (ED50=62.5 mg/kg) was most active. Among the tested compounds, 2a-c, 3a, and 3b showed anticonvulsant activities in the MES and PTZ test. All of the tested compounds, except 2f and 3f, showed significant anticonvulsant activities in the MES or PTZ test. In addition, the neurotoxicities of these compounds were comparable to other anticonvulsant drugs.

Synthesis and anticonvulsant activity of some (2/4-substituted)benzaldehyde (2-oxobenzothiazolin-3-yl)acetohydrazones

Fifteen new (2/4-substituted)benzaldehyde (2-oxobenzothiazolin-3-yl)acetohydrazones were synthesized and their structures were elucidated by NMR and elemental analysis. Their anticonvulsant activity was tested by a pentylenetetrazole induced seizure test. Compounds 4e and 4h were found to be the most promising among the others.

The effect of N-substituted alkyl groups on anticonvulsant activities of N-Cbz-alpha-amino-N-alkylglutarimides.

In order to examine the effects of N-substituted alkyl group on the anticonvulsant activities of N-Cbz-alpha-aminoglutarimides as novel anticonvulsants with broad spectrum, a series of (R) or (S) N-Cbz-alpha-amino-N-alkylglutarimides (1 and 2) were prepared from the corresponding (R) or (S) N-Cbz-glutamic acid and evaluated for the anticonvulsant activities in the maximal electroshock seizure (MES) test and pentylenetetrazol induced seizure (PTZ) test, including the neurotoxicity. The most potent compound in the MES test was (S) N-Cbz-alpha-amino-N-methylglutarimide (ED50=36.3 mg/kg, PI=1.7). This compound was also most potent in the PTZ test (ED50=12.5 mg/kg, PI=5.0). The order of anticonvulsant activities against the MES test as evaluated from ED50 values for (R) series was N-methyl > N-H > N-ethyl > N-allyl; for the (S) series N-methyl > N-H > N-ethyl > N-allyl > N-isobutyl compound. Against the PTZ tests, the order of anticonvulsant activities showed similar pattern; for the (R) series, N-methyl > N-H > N-ethyl > N-allyl; for the (S) series N-methyl > N-H > N-ethyl > N-allyl > N-isobutyl compound. From the above results, N-substituted alkyl groups were thought to play an important role for the anticonvulsant activities of N-Cbz-alpha-amino-N-alkylglutarimides.

The effect ofN-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-α-aminoglutarimides.

In connection with the development of new anticonvulsant agents with a broad spectrum, we reported thatN-Cbz-α-aminoglutarimides, combining common structures of other anticonvulsants such as N-CO-C-N and cyclic imides in a single molecule, showed significant anticonvulsant activities in the MES (maximal electroshock seizure) and PTZ (pentylenetetrazole induced seizure) tests. In these studies, a series of (R) and (S)N-alkyloxycarbonyl-α-aminoglutarimides7a∼7e and8a∼8e, which were substituted with various alkyloxycarbonyl group instead ofCbz group, were prepared from the corresponding (R) and (S)N-Cbz-glutamic acid3 and4, and were evaluated with their anticonvulsant activities against the MES and PTZ tests, including neurotoxicity, in order to define the effect ofN-alkyloxycarbonyl group on the anticonvulsant activities ofN-alkyloxycarbonyl-α-aminoglutarimides. Among them, (S)N-4-nitrobenzyloxycarbonyl-α-amino-N-methylglutarimide8e was the most active in MES (ED50=35.6 mg/kg, Pl=2.7) and PTZ tests (ED50=15.6, Pl=6.1). Interestingly, (R) and (S)N-4-nitrobenzyloxycarbonyl-α-amino-N-methylglutarimide7e and8e and (R)N-phenoxycarbonyl-α-amino-N-methylglutrimide7d showed significant anticonvulsant activities in both the MES and PTZ tests and other compounds showed anticonvulsant activities in only the PTZ test. In addition, it was found that their anticonvulsant activities were dependent on their stereochemistries andN-substituted alkyloxycarbonyl groups.

Synthesis and anticonvulsant properties of triazolo- and imidazopyridazinyl carboxamides and carboxylic acids

Analogues of 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine PC25 containing amide or carboxylic acid function were synthesized and tested for anticonvulsant activity. The compounds having the imidazole ring substituted with an amide group have been found to be generally more active against maximal electroshock-induced seizures in mice (15.2≤ ED50 ≤ 37.5mgkg−1 orally). Furthermore, maximum activity was generally associated with a 2,6-dichlorobenzyl substitution pattern. 3-Amido-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine 4b was also protective in the pentylenetetrazole-induced seizures test (ED50=91.1mgkg−1 orally) and blocked strychnine-induced tonic extensor seizures (ED50=62.9mgkg−1 orally). Moreover, calculated electrostatic isopotential maps of the whole active compounds were quite similar and, consequently, could be associated to optimum anticonvulsant activity.

Examination of the potential antiepileptic activity of calcium antagonists with different sites of action

1. 1. Calcium is proposed to play a role in the genesis of epileptic seizures, and a number of established antiepileptic drugs limit the transport of extracellular calcium into neuronal cells. 2. 2. The aim of the present study was to explore the potential antiepileptic activity of three calcium antagonists: nifedipine (20 mg/kg i.p.), which blocks the calcium channel at its outer mouth; verapamil (30 mg/kg i.p.), which blocks the calcium channel at its inner mouth; and propyl-methylenedioxyindene (pr-MDI; 68, 100 and 120 mg/kg i.p.), which acts intracellularly to inhibit calcium mobilization from the endoplasmic reticulum. 3. 3. In the maximal electroshock test, none of the calcium antagonists provided protection against tonic seizures in mice. Phenytoin (20 mg/kg i.p.), on the other hand, afforded complete protection. 4. 4. In the pentylenetetrazol-induced seizure test, the order of effectiveness of the three calcium antagonists in attenuating the severity of the clonic and tonic seizures in mice was: nifedipine > verapamil > pr-MDI. All three calcium antagonists were less effective than ethosuximide (200 mg/kg i.p.). 5. 5. These findings indicate that the calcium antagonists would be of no value in the treatment of grand mal epilepsy, while only those agents acting at the outer side of the membrane would have limited usefulness at best against petit mal seizures.