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PubMed1996

3-Phenyl-substituted imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas that have high affinity at the GABAA/benzodiazepine receptor complex.

A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, although most analogs were partial agonists as indicated by [35S]TBPS and Cl- current ratios. Interestingly, a subseries of piperazine ureas was identified which had biphasic efficacy, becoming more antagonistic with increasing concentration. Analogs within the imidazo[1,5-alpha]quinoxalin-4-one series had substantially decreased binding affinity as compared to the quinoxaline urea series. These compounds ranged from antagonists to full agonists by in vitro analysis, with several derivatives having roughly 4-fold greater intrinsic activity than diazepam as indicated by Cl- current measurement. Numerous compounds from both series were effective in antagonizing metrazole-induced seizures, consistent with anti-convulsant properties and possible anxiolytic activity. Most of the quinoxaline ureas and quinoxalin-4-ones were active in an acute electroshock physical dependence side effect assay in mice precluding further development.

Animals↗

PubMed1996

High-affinity alpha-aminobutyric acid A/benzodiazepine ligands: synthesis and structure-activity relationship studies of a new series of tetracyclic imidazoquinoxalines.

A series of tetracyclic imidazoquinoxaline analogs was developed which constrain the carbonyl group of the partial agonist 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-[(dimethylamino)carbonyl] - 4,5-dihydroimidazo[1,5-alpha]quinoxaline (2, U-91571) away from the benzene ring. These analogs orient the carbonyl group in the opposite direction of the previously reported full agonist 1-(5- cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazo[1,5- alpha]pyrrolo [2,1-c]quinoxalin-10(11H)-one (3, U-89267). A number of approaches were utilized to form the "bottom" ring of this tetracyclic ring system including intramolecular cyclizations promoted by Lewis acids or base, as well as metal-carbenoid conditions. The size and substitution pattern of the additional ring was widely varied. Analogs within this series had high affinity for the benzodiazepine receptor on the alpha-aminobutyric acid A chloride ion channel complex. From TBPS shift and Cl- current assays, the in vitro efficacy of compounds within this class ranged from antagonists to partial agonists with only 18a identified as a full agonist. Additionally, several analogs were quite potent at antagonizing metrazole-induced seizures indicating possible anticonvulsant or anxiolytic activity. Unlike 3, analogs in this series did not have high affinity for the diazepam insensitive alpha 6 beta 2 delta 2 subtype. These results suggest that either constraining the carbonyl group away from the benzene ring or the greater planarity that results from the additional cyclic structure provides analogs with partial agonist properties and prevents effective interaction with the alpha 6 beta 2 delta 2 subtype.

Animals↗

PubMed1996

Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine-pyridinium salt redox chemical delivery system.

3-(2-Hydroxyethyl) 5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedi-carboxyla te (7) was prepared using a modified Hantzsch reaction, which was then elaborated to 3-[2-[[(1-methyl-1,4-dihydropyrid-3-yl)carbonyl]oxy]ethyl]5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylat e [10, felodipine-chemical delivery system (CDS)]. The equipotent 3-(2-hydroxyethyl) 7 (IC50 = 3.04 x 10(-8) M) and felodipine-CDS (10, IC50 = 3.10 x 10(-8) M) were, respectively, 2- and 21-fold less potent calcium channel antagonists than the reference drugs nimodipine (IC50 = 1.49 x 10(-8) M) and felodipine (IC50 = 1.45 x 10(-9) M). Compounds 7, 10, nimodipine, and felodipine are highly lipophilic (Kp = 236, 366, 187, and 442, respectively). 3-(2-Hydroxyethyl) 7, felodipine-CDS (10), and felodipine provided protection against maximal electroshock-induced seizures in mice but were inactive in the subcutaneous metrazol anticonvulsant screen. In vitro incubation studies of felodipine with rat plasma and 20% brain homogenates showed felodipine was very stable in both biological media. Similar incubations of felodipine-CDS showed its rate of biotransformation followed psuedo-first-order kinetics with half-lives of 15.5 h in rat plasma and 1.3 h in 20% rat brain homgenates. In vivo biodistribution of felodipine and felodipine-CDS was studied. Uptake of felodipine in brain produced a peak brain concentration of 5 micrograms/g of brain tissue at 5 min, after which it rapidly egressed from brain resulting in undetectable levels at 60 min. Peak blood concentrations of 10 occurred at about 7 min followed by a rapid decline to a near undetectable concentration by 17 min. The pyridinium salt species 9, resulting from oxidation of 10, also reached peak concentrations at about 7 min but it slowly decreased to undetectable concentrations at 2 h. 3-(2-Hydroxyethyl) 7 remained at near undetectable concentrations throughout a 2 h time period. Localization of 10 in brain provided a peak concentration of 4.2 micrograms/g of brain tissue at 5 min and then decreased to negligible concentrations at 15 min. The concentration of oxidized pyridinium species 9 in brain remained high providing detectable concentrations up to 4 days. In contrast, the concentration of the 3-(2-hydroxyethyl) hydrolysis product 7 in brain remained at very low levels throughout the study. The slow hydrolysis rate of the pyridinium ester 9 to the 3-(2-hydroxyethyl) 7 and the rapid egression of felodipine-CDS from brain are believed to contribute to the moderate anticonvulsant activity exhibited hy the felodipine-CDS (10).

Animals↗

PubMed1999

Piperazine imidazo[1,5-a]quinoxaline ureas as high-affinity GABAA ligands of dual functionality.

A series of imidazo[1,5-a]quinoxaline piperazine ureas appended with a tert-butyl ester side chain at the 3-position was developed. Analogues within this series have high affinity for the gamma-aminobutyric acid A (GABAA)/benzodiazepine receptor complex with efficacies ranging from inverse agonists to full agonists. Many analogues were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Uniquely, a number of these analogues were found to have a bell-shaped dose-response profile in the alpha1 beta2 gamma2 subtype as determined by whole cell patch-clamp technique, where in vitro efficacy was found to decrease with increasing drug concentration. Many of the compounds from this series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant and possibly anxiolytic activity. Additionally, several analogues were also effective in lowering cGMP levels (to control values) after applied stress, also consistent with anxiolytic-like properties. The most effective compounds in these screens were also active in animal models of anxiety such as the Vogel and Geller assays. The use of the piperazine substituent allowed for excellent drug levels and a long duration of action in the central nervous system for many of the quinoxalines, as determined by ex vivo assay. Pharmacokinetic analysis of several compounds indicated excellent oral bioavailability and a reasonable half-life in rats. From this series emerged two partial agonists (55, 91) which had good activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.

Animals↗

PubMed2003

Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy.

PURPOSE: Racemic valnoctamide (VCD) is a central nervous system-active drug commercially available in Europe. VCD possesses two chiral centers and, therefore, it exists as a mixture of four stereoisomers. The purpose of this study was to evaluate the anticonvulsant activity of two VCD stereoisomers in comparison with VCD (racemate), valpromide (VPD), and valproic acid (VPA) and to study their pharmacokinetic-pharmacodynamic relationships. METHODS: The ability of racemic VCD, (2S,3S)-VCD, (2R,3S)-VCD and VPD to block partial seizures was studied in the 6Hz psychomotor seizure model in mice and in the hippocampal kindled rat. The ability of (2S,3S)-VCD and (2R,3S)-VCD to prevent generalized seizures was evaluated in the maximum electroshock (MES) and subcutaneous metrazole (sc Met) seizure tests. The PK of (2S,3S)-VCD, (2R,3S)-VCD, and VPD was studied in the mice utilized in the 6Hz model. RESULTS: All of the tested compounds were effective in the models tested. No significant difference in ED50 values was observed but the plasma and brain EC50 values of (2R,3S)-VCD in the 6Hz model at 32 mA stimulation were 2-fold higher than the EC50 values of (2S,3S)-VCD. An excellent pharmacokinetic-pharmacodynamic correlation was found between the plasma and brain concentrations of the VCD stereoisomers and their anticonvulsant effect in mice. Stereoselectivity was observed in clearance, volume of distribution, and in brain-to-plasma AUC ratio at a dose of 25 mg/kg, but the difference disappeared at higher doses as the clearance of the stereoisomers decreased and their half-life increased. For (2R,3S)-VCD the brain-to-plasma AUC ratio doubled at the tested dose range, while it remained constant for (2S,3S)-VCD. CONCLUSIONS: Racemic VCD, VPD, (2R,3S)-VCD, and (2S,3S)-VCD are effective anticonvulsants in animal models of partial seizures and are more potent than VPA. The more favorable brain penetration of (2S,3S)-VCD and its lower EC50 value in the 6Hz test provides one advantage over (2R,3S)-VCD as a new antiepileptic drug.

Amides↗

PubMed2004

Synthesis of some mono-Mannich bases and corresponding azine derivatives and evaluation of their anticonvulsant activity.

Mono-Mannich bases, 3-amino-1-aryl-1-propanone hydrochlorides (Ig1-Ig4), and their corresponding azine derivatives, N,N'-bis(3- amino-1-aryl-propylidene) hydrazine dihydrochlorides (D1-D4), were synthesized and their anticonvulsant activities were evaluated. Alterations in biological activity depending on modifications in chemical structure were also followed. The aryl part was phenyl in Ig1, D1, Ig2, D2, Ig3, D3, or p-hydroxyphenyl in Ig4, and D4. The amine part was dimethylamine in Ig1, D1, Ig4, and D4, piperidine in Ig2, D2 or morpholine in Ig3, D3. Compounds D2, D3, and D4 are new. The anticonvulsant activity was determined by maximal electroshock (MES) and subcutaneous metrazole (pentetrazol; scMet) tests. The rotorod toxicity test was used for determining neurological deficits. While the compounds were not effective in scMet, they were found to exert protective effect in MES. The results of MES are as follows: Compound [dose level (mg/kg), time (h)]: Ig1 [30 (0.5 h), 100 (0.5 h)]; Ig2 [30 (0.5 h, 4 h)]; Ig3 [30 (0.5 h), 100 (0.5 h), 300 (0.5 h, 4 h)]; Ig4 [300 (0.5 h, 4 h), 100 (4 h)]; D1 [30 (0.5 h)]; D3 [100 (0.5 h,4 h), 300 (0.5 h), 30 (4 h)]]; D4 [300 (0.5 h, 4 h)]. D2 did not show any anticonvulsant activity in both tests. Ig1, Ig2, D1, D2, and D3 exhibited neurotoxicity. Compounds Ig2, D1, and D2 were neurotoxic at 100 mg/kg dose level at 0.5 h. Ig1 was neurotoxic at 300 mg at 0.5 h, D3 was neurotoxic at 300 mg at 4 h. Conversion of mono-Mannich bases to their corresponding azine derivatives generally decreased the anticonvulsant activity. Ig3, Ig4 and D4 seem to be promising candidates to develop new anticonvulsant compounds for grand mal epilepsy for further synthesis and in vivo studies, since they were effective in MES screening and no neurotoxicity was observed with them.

Animals↗

PubMed2002

Synthesis and evaluation of anticonvulsant activities of some bis Mannich bases and corresponding piperidinols.

Some acetophenone derived bis Mannich bases (B1-B5) and piperidinols (C1, C4), which are the structural isomers of B1 and B4, and also quaternary piperidine derivative C6 were synthesized and studied for anticonvulsant activity. Of the compounds, C6 was reported for the first time. Chemical structures of the compounds were confirmed by UV, IR, 1H-NMR, 13C-NMR, mass spectra and elemental analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) tests and rotarod test for neurological deficits. According to the activity studies, B2, B4, C1 and C4 derivatives were found to be protective against MES at 30 mg/kg and above. B1, B2, B3, B4, C4 and C6 derivatives were found to be protective against scMet. at different dose levels ranging from 30 to 300 mg/kg. Since no neurotoxicity was detected for the compounds B4 and C4, they seem to be candidate compounds for further synthesis and in vivo studies for their potential anticonvulsant activity.

Animals↗

PubMed2001

Synthesis and evaluation of anticonvulsant activities of some new arylhexahydropyrimidine-2,4-diones.

In this study, some new 3-alkyl-6-arylhexahydropyrimidine-2,4-dione derivatives were synthesized as anticonvulsant agents. 6-Arylhexahydropyrimidine-2,4-diones which were used as starting materials in the synthesis of the compounds were prepared in acidic media by the cyclization of potassium cyanate and the appropriate ureido acids that were gained by the reaction of beta-aminoacids, malonic acid and ammonium acetate. The structures of the synthesized compounds were confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 3-arylalkyl-6-(p-chlorophenyl) derivatives were found to be protective against scMet, whereas 6-phenyl derivatives were not. 6-Phenyl-3-(2-morpholinoethyl)hexahydropyrimidine-2,4-dione was the only compound determined to be active against MES at 300 mg/kg dose at half an hour.

Alkanes↗

PubMed1988

Convulsant-induced increase in transcription factor messenger RNAs in rat brain.

Administration of the convulsants pentylenetetrazole (Metrazole) or picrotoxin to rats caused a dramatic increase in mRNAs of four putative transcription factor genes, zif/268, c-jun, jun-B, and c-fos, in neurons of the hippocampus and dentate gyrus, as well as other areas of the cerebral cortex, including pyriform cortex and cingulate cortex. The increase in these mRNAs was rapid and transient: amounts peaked within 1 hr and returned to baseline within 2 hr. These results extend the observation made by Morgan et al. [Morgan, J. I., Cohen, D. R., Hempstead, J. L. & Curran, T. (1987) Science 237, 192-197] that c-fos mRNA and protein are induced in rat brain after seizures. We hypothesize that the increase of these putative transcription factor mRNAs in the brain is part of a programmed genomic response of neurons to intense stimulation, which is analogous to the genomic response of nonneuronal cells to growth factors.

Animals↗

PubMed1981

Lidocaine and pentylenetetrazol seizure thresholds in cats are not reduced after enflurane anesthesia.

Some previous reports indicate that the excitability of the brain may be increased for days following enflurane anesthesia. The authors investigated this possibility in cats by determining whether or not pentylenetetrazol- (Metrazol) or lidocaine-seizure thresholds decreased after repeated enflurane exposure. The lidocaine-seizure threshold was bracketed in 4 cats, and the pentylenetetrazol-seizure threshold was bracketed in another 4 cats. Each cat was then exposed to 4 per cent enflurane for 2 hours on 4 successive days. Twenty-four hours after the last enflurane exposure, the cats were injected with the previously determined subthreshold dose of pentylenetetrazol (6.4 mg/kg, on the average) or lidocaine (7.8 mg/kg, on the average). No cat convulsed. It was therefore concluded that under our experimental conditions, repeated enflurane exposure does not increase the sensitivity to drugs which nonselectively excite the central nervous system (e.g., pentylenetetrazol) or to drugs which mimic temporal lobe epilepsy (e.g., lidocaine). This finding cast doubt that brain excitability is increased in the post-enflurane anesthetic period.

Anesthesia↗

PubMed2002

Stimulus-specific induction of an Egr-1 transgene in rat brain.

Regulated expression of Egr-1 (Zif268/NGFIA) in a variety of brain networks suggests a diversity of roles in neuronal plasticity. Here, we aimed to determine whether an egr-1 transgene would mediate transcriptional responses to different pharmacological and physiological stimuli in the brain of transgenic rats. Constitutive transgene expression was observed in the cortex, CA1 hippocampal area and pituitary, recapitulating expression of egr-1. Transgene induction was stimulus-specific. Metrazole induced widespread expression in the dentate gyrus, CA2 and CA3 areas, amygdala, and ventromedial nucleus. In contrast, induction following a light stimulus was restricted to the hypothalamic suprachiasmatic and periventricular nuclei. Our studies have provided novel insights into the differential regulation of egr-1, and facilitated approaches to the genetic manipulation of Egr-1-regulated neuronal systems.

Animals↗

PubMed1989

Fos-Like Immunoreactivity Induced by Seizure in Mice Is Specifically Associated With Euchromatin in Neurons.

Administration of convulsant drugs causes the rapid induction of c-fos in identified neurons within the mouse central nervous system (Morgan et al., 1987). In particular, Fos-like immunoreactivity is evident in nuclei of granule cells of the hippocampal dentate gyrus within 30 minutes of the onset of seizure. By immunoelectron microscopy, Fos antibody binding was exclusively localized to dispersed chromatin (euchromatin) of several types of projection neurons and local circuit neurons in various brain regions and especially in the dentate gyrus, 210 minutes after a single injection of Metrazol. Fos-like immunoreactivity was not detectable in the nucleolus, nor in the characteristic peripheral and nucleolus-associated heterochromatin of hippocampal granule cells. No immunostaining was observed in nuclei of glial, ependymal or endothelial cells, and no cytoplasmic reactivity was seen in any cell type. These findings support a role for Fos in stimulus-response coupling at the level of transcriptional regulation in neurons.

Journal Article↗

PubMed1981

Convulsant-specific architecture of the postictal behavior syndrome in the rat.

The postictal immobility syndrome was examined in five experimental grand mal epilepsy models in an attempt to analyze separately the behavioral and underlying neurochemical aspects of the rigid-catatonic and flaccid-cataleptic states. Catalepsy and analgesia were found in varying degrees after maximal electroshock (MES), metrazol, picrotoxin, and Ro 5-3663 activated seizures. Signs of rigidity were noticed after the MES and picrotoxin seizures. Kindled seizures were followed by explosive behavior without signs of rigidity, catalepsy, and analgesia. Naloxone reduced the duration but not the score (intensity) of catalepsy and failed to selectively antagonize analgesia. The relative representation of the tonic stage of convulsions seemed to be the major determinant of the development of catatonic-cataleptic symptomatology. It is suggested that more than a single neurotransmitter system is involved in the postictal immobility syndrome and each epilepsy model has its unique neurochemical profile.

Animals↗

PubMedDate not supplied

Triazolines XV. Anticonvulsant profile of ADD 17014, a potentially unique 1,2,3-triazoline antiepileptic drug, in mice and rats.

ADD 17014[1-(4-chlorophenyl)-5-(4-pyridyl) delta 2-1,2,3-triazoline], is a representative member of a hitherto unknown, structurally novel family of anticonvulsant agents. The anticonvulsant profile of ADD 17014 following intraperitoneal (i.p.) and oral administration in mice and rats was evaluated using a battery of well-standardized anticonvulsant tests and compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). The results indicate that ADD 17014 is effective in nontoxic i.p. doses in mice by the maximal electroshock seizure (MES), Metrazol (subcutaneous, s.c. Met), bicuculline (s.c. Bic) and picrotoxin (s.c. Pic) tests, but ineffective against strychnine-induced seizures; it is also effective after nontoxic oral doses in both mice and rats by the MES and s.c. Met tests. Protective indices (PI = TD50/ED50), calculated from i.p. data in mice, were highest for ADD 17014 by the s.c. Met (26.02) and s.c. Bic (93.93) tests; the PIs, after oral administration in mice and rats, were equal to or higher than those of the prototype agents. In vitro receptor binding studies of ADD 17014 and potential metabolites indicated no significant inhibitory activity except for the beta-amino alcohol, which displaced almost 93% of [3H]glutamate from the glutamate receptors, suggesting that ADD 17014 may be functioning as a prodrug and an excitatory amino acid antagonist. The overall results indicate that ADD 17014 is a relatively nontoxic agent that more closely resembles PB and VPA, with a broad and unique spectrum of anticonvulsant activity.

Animals↗

PubMedDate not supplied

Quantum pharmacologic studies applicable to the design of anticonvulsants: theoretical conformational analysis and structure-activity studies of barbiturates.

We report the first large-scale systematic quantitative structure-activity relationship (QSAR) study of barbiturates, correlating molecular structures with anticonvulsant activity. To achieve this QSAR study, we devised a four-step strategy. In step 1, an optimal quantum mechanical technique for determining the geometry and shape (conformation) of barbiturates was ascertained; this is the AM1 semiempirical molecular orbital method. In step 2, the AM1 method was used to optimize the structures and molecular properties of 48 barbiturates with varying anticonvulsant activity. In step 3, discriminant analysis and regression analysis statistical calculations were used to correlate the molecular properties of the 48 analogues against maximal electroshock (MES) and subcutaneous metrazol (s.c.Met)-induced seizures. In step 4, the contribution of molecular electrostatic properties to barbiturate anticonvulsant activity was further refined by quantum mechanical derived molecular electrostatic potential (MEP) maps. Using this four-step strategy, we defined the pharmacophore, the portion of a molecule responsible for bioactivity, for anti-MES and anti-s.c.Met activity. For anti-s.c.Met activity, barbiturate lipophilicity and geometry are important considerations; for anti-MES activity, barbiturate topologic and electronic properties have increased relevance.

Anticonvulsants↗

PubMed1995

Development of epileptic activity in embryos and newly hatched chicks of the Fayoumi mutant chicken.

The homozygous Fayoumi strain of epileptic chickens (Fepi) is affected by generalized convulsions consistently induced by intermittent light stimulation (ILS) and by intense sound. Although interictal EEG recordings show continuous spikes and spike and wave activity, desynchronization and flattening (DF) of the EEG are observed during seizures. We have studied development of the epileptic phenotype in embryonic (E) and posthatching (P) Fepi. As compared with those of chicken embryos of a normal strain, no differences were observed in the EEG before embryonic day (E) 16. Clearly differentiated spikes and spike and waves appeared at E17 in Fepi. Metrazol-induced EEG seizures were observed at E16 in normal embryos and at E17 in Fepi. The Fepi showed some characteristics: Spontaneous EEG seizure-like discharges also appeared at E17 but decreased toward hatching; visual or acoustic hyperexcitability developed at E20 together with evoked responses in normal chickens; desynchronization of the EEG, typical of the epileptic seizure of the adult, could be induced by ILS at B20, but ILS- or sound-induced generalized motor seizures appeared at P1, a few hours after hatching. Results show that Fepi phenotype reaches full expression at P1, but the electric paroxysms are expressed earlier, paralleling synaptic maturation.

Animals↗

PubMed1999

Structure-pharmacokinetic-pharmacodynamic relationships of N-alkyl derivatives of the new antiepileptic drug valproyl glycinamide.

PURPOSE: The purpose of this study was to evaluate the structure-pharmacokinetic-pharmacodynamic relationships of a series of N-alkyl and N,N-dialkyl derivatives of the new antiepileptic drug (AED), valproyl glycinamide (VGD). METHODS: The following compounds were synthesized: N-methyl VGD (M-VGD), N,N-dimethyl VGD, N-ethyl VGD, N,N-diethyl VGD (DE-VGD), and N,N-diisopropyl VGD. These compounds were evaluated for anticonvulsant activity, neurotoxicity, and pharmacokinetics. RESULTS: After i.p. administration to mice in the maximal electroshock seizure test (MES), DE-VGD had an ED50 value comparable to that of VGD (145 and 152 mg/kg, respectively), whereas in the subcutaneous metrazol test (sc Met) model, M-VGD had a slightly lower ED50 than VGD (108 and 127 mg/kg, respectively). After oral administration to rats, M-VGD had an MES-ED50 similar to that of VGD (75 and 73 mg/kg, respectively). Of the N-alkyl VGD derivatives studied, M-VGD had the best pharmacokinetic profile: the lowest clearance (5.4 L/h), the longest half-life (1.8 h), and the lowest liver-extraction ratio (14%). N,N-dialkylated VGD derivatives underwent two consecutive N-dealkylations, whereas N-alkylated derivatives underwent a single N-dealkylation process, yielding VGD as a major active metabolite. CONCLUSIONS: M-VGD had the most favorable pharmacodynamic and pharmacokinetic profile of the investigated N-alkyl VGD derivatives. VGD was found to be a major active metabolite of M-VGD and to be less neurotoxic than M-VGD. Therefore VGD rather than one of the investigated N-alkyl VGD derivatives should be considered for development as a new AED.

Alkylation↗

PubMed1966

Sleep: suppression of rapid eye movement phase in the cat after electroconvulsive shock.

Electroconvulsive shock, administered for 5 to 7 days, reduced the daily rapid eye movement sleep time of seven cats to as little as 28 percent of base line levels. After day 4, eye movements during periods of cortical activation without tonic electromyographic activity were greatlyreduced. Although partially deprived of rapid eye movements for as long as 7 days, the cats showed no compensatory rise in rapid eye movement time during the recovery period, but controls equally deprived gave significant rebounds. Rapid eye movement time of anesthetized cats was not affected by current that usually produces con vulsions; it was lowered in animals convulsed with metrazol, but the same dosage of this drug, administered so as to avoid convulsions, had little eflect. It appears that some aspect of the convulsion is responsible for lowering the rapid eye movement time.

Animals↗