Synthesis and GABA(A) receptor activity of a 6,19-oxido analogue of pregnanolone.

3 alpha-Hydroxy-6,19-oxidopregn-4-ene-20-one (4) was prepared in seven steps from pregnanolone acetate. At 0.1 microM concentration 4 significantly increased GABA induced (36)Cl(-) influx in hamster cerebral cortex synaptoneurosomes while at 20 mg/kg it decreased the percentage of hamsters showing seizures induced by 3-mercaptopropionic acid.

Time-dependent anticonvulsant activity of melatonin in hamsters.

The objective of the present study was to assess whether the anticonvulsant activity of melatonin displays diurnal variability in hamsters. Convulsions were induced by administering 3-mercaptopropionic acid (3-MP). There was a significant diurnal variation in 3-MP-induced convulsions, hamsters being more prone to exhibit seizures during the night than during the day. Melatonin (50 mg/kg i.p.) had a maximal anticonvulsive effect in the early evening (20:00 h). The administration at 20:00 h of the central-type benzodiazepine antagonist, Ro 15-1788, although unable by itself to modify seizure threshold, blunted the anticonvulsant response to melatonin. The results indicate that the time-dependent anticonvulsant activity of melatonin is sensitive to central-type benzodiazepine antagonism.

Synthesis and anticonvulsant activity of some benzopyranone imino derivatives of GABA and related compounds.

The synthesis of some 5-hydroxy-4-imino-2,3-dihydrobenzopyran derivatives of GABA and alkylamines is described. The products were tested for their GABA-receptor binding and anticonvulsant activity in mice. Some compounds showed anticonvulsant activity. No binding to GABA receptors was observed.

A novel class of "GABAergic" agents: 1-aryl-3-(aminoalkylidene)oxindoles.

Antagonism of mercaptopropionic acid (MPA) induced convulsions, reflecting a GABAergic mechanism, was observed in a series of 1-aryl-3-(aminoalkylidene)oxindoles. Optimal MPA antagonism was associated with 3-halo, 3-alkyl, and/or 4-alkoxy substituents in the pendant aryl ring and with (dimethylamino)methylene, 1-(dimethylamino)-ethylidene and N-methyl-2-pyrrolidinylidene side chains. The precise mechanism of action of these agents is unclear at this time; however, they are not GABA mimics and they do not affect GABA levels. Like other GABAergic agents, these compounds are potent enhancers of benzodiazepine binding and they antagonize cyclic GMP elevations induced by isoniazid. Compounds from this series may therefore have potential therapeutic utility as anticonvulsants or anxiolytics.

Proline and proline derivatives as anticonvulsants.

1. The anticonvulsant properties of L-proline, of proline derivatives (trans-4-hydroxy-L-proline, cis-4-hydroxy-D-proline, 3,4-dehydro-D,L-proline) and of D- and L-pipecolic acid were studied alone and in combination with vigabatrin (R/S-4-aminohex-5-enoic acid). 3-Mercaptopropionic acid and pentylenetetrazol-induced convulsions in mice were used as animal models of epilepsy. 2. Proline and proline derivatives are weak anticonvulsants if given alone in doses up to 10 mmol/kg, however, they are capable of potentiating the anticonvulsant effects of vigabatrin, in a manner similar to that reported previously for glycine, and some glycine derivatives. Among the compounds tested, trans-4-hydroxy-L-proline was the most potent anticonvulsant in combination with the indirect GABA agonist vigabatrin. 3. A potential explanation for the synergistic anticonvulsant effect of the combination of the GABA agonist and proline is the presumed role of proline as inhibitory neurotransmitter, and/or its glutamate antagonistic effects. 4. The current study points out the lack of basic knowledge on the neurochemistry and pharmacology of proline and hydroxyproline.

GABA-ergic mechanisms in the anticonvulsive activity of newly-synthesized barbiturates. I. Effects of barbiturates on the convulsive action of GABA-antagonists.

The anticonvulsive activity of seven newly-synthesized derivatives of barbituric acid, having a hydroxylamins groups substituted in second position, with respect to convulsive agents related with the GABA-ergic transmitter system: picrotoxin, bicuculline, thiosemicarbazide and 3-mercaptopropionic acid, was studied in experiments on mice. The anticonvulsive activity of these compounds in allylglycine-induced convulsions was investigated in experiments on rats, and was compared to that of well-known drugs, such as pentobarbital, phenobarbital, allobarbital and diphenylhydantoin. The results obtained show that the hydroxylamine derivatives of barbituric acid HB-2 (2-hydroxylamino-5-ethyl-5-propylbarbituric acid) and HB-7 (2-hydroxylamino-5-ethyl-5 sec. pentylbarbituric acid) have the most pronounced anticonvulsive activity, which suggests the considerable importance of the participation of GABA-ergic transmission in the realization of this activity.

Anticonvulsant and convulsant properties of flurazepam.

The anticonvulsant efficacy of the benzodiazepine flurazepam was tested in rats treated with a convulsant dose of either picrotoxin or 3-mercaptopropionic acid. Against picrotoxin, a significant anticonvulsant effect was observed in the range of 30-60 mg/kg, i.p. Epileptogenicity increased as doses of flurazepam were increased from 60 to 200 mg/kg, and at a dose of 400 mg/kg all subjects died. In similar tests, the benzodiazepines clonazepam and triazolam produced only dose-dependent increases in anticonvulsant efficacy. Flurazepam also proved to be an effective anticonvulsant in tests against 3-mercaptopropionic acid. The results of this study provide further evidence that benzodiazepines have varying degrees of epileptogenicity.

Effects of the glutamic acid decarboxylase inhibitor 3-mercaptopropionic acid on the synthesis of brain GABA in vivo and postmortally.

The effects of the glutamic acid decarboxylase inhibitor 3-mercaptopropionic acid (MPA) on the concentration of GABA in the mouse brain were studied. MPA completely inhibited the postmortem increase in GABA. This effect was used in order to achieve a maximal inhibition of the GABA synthesis in vivo during 67.5 minutes before killing by giving the drug repeatedly (50 mg/kg + 6 X 10 mg/kg i.p.) to mice pretreated with chloral hydrate (100 mg/kg i.p., 65 min before killing). Such a treatment with MPA markedly reduced the accumulation of GABA following inhibition of the GABA transaminase by aminooxyacetic acid but it did not change the endogenous concentration of GABA. This discrepancy might be due to inhibition of the impulse--evoked release of GABA following MPA.

GABA-like actions of levonantradol.

The interaction of levonantradol and its pharmacologically less active (+)-enantiomer with GABAergic mechanisms was studied in several in vivo systems: (1) rat cerebellar cGMP, based on the inverse relationship of GABAergic activity and cGMP levels; (2) convulsions elicited by 3-mercaptopropionic acid, an inhibitor of GABA synthesis; and (3) activated dopamine synthesis in rat striatum following blockade of dopamine receptors. Levonantradol decreased rat cerebellar cGMP content at low doses (1.0 mg/kg intraperitoneally) and antagonized elevation of cGMP levels by the GABA biosynthesis inhibitor isoniazid at even lower doses (0.32 mg/kg intraperitoneally); this activity pattern is suggestive of GABAergic activity. This conclusion is also supported by levonantradol's protection of mice against the convulsant effects of 3-mercaptopropionic acid, GABAergic agents are known to antagonize the enhanced dopamine synthesis and turnover that accompany dopamine receptor blockade by neuroleptics. Levonantradol (0.047 mg/kg intravenously) stereospecifically attenuated the elevated dopa accumulation induced by haloperidol. Levonantradol is at least 100-fold more active than THC in blocking isoniazid-induced elevation of cGMP levels in rat cerebellum or haloperidol-induced enhanced dopa accumulation in rat striatum.

[Further study of the antiepileptic properties of nicotinamide]. / Dal'neishee izuchenie protivoépilepticheskikh svoistv nikotinamida.

Acute experiments on cats have shown that nicotinamide (100-500 mg/kg) injected intravenously suppresses the epileptic activity in solitary foci produced in the cortex by application for several seconds of a 0.5% solution of penicillin as well as in the complex of foci produced by application of a 0.1--3% solution of strychnine to various cortical zones. Nicotinamide (500-100 mg/kg) does not affect the character of the epileptic activity of foci created by application of 1% penicillin to the cerebral cortex or on the generalized epileptic activity produced by application of concentrated solutions of strychnine or penicillin. In an epileptic focus produced by application of 5-10% acetylcholine and 0.5% proserine, injection of nicotinamide leads at first to the disappearance of after-effect discharge and then of spike potential. It is concluded that nicotinamide has an antiepileptic activity.