Anticonvulsant 1-phenylcycloalkylamines: two analogues with low motor toxicity when orally administered.

1-Phenylcyclohexylamine (PCA) and its analogues 1-phenylcyclopentylamine (PPA) and 1-(3-fluorophenyl)cyclohexylamine (3-F-PCA) are potent anticonvulsants in the mouse maximal electroshock (MES) seizure test. Unlike the structurally related dissociative anesthetic phencyclidine (PCP), however, which produces motor toxicity at anticonvulsant doses, PCA, PPA, and 3-F-PCA protect against MES seizures at 2.2- to 3.5-fold lower doses than those that cause motor toxicity when administered intraperitoneally (i.p.). In the present study, we evaluated the oral anticonvulsant activity of PCA, PPA, and 3-F-PCA in mice; we also examined 3-F-PCA in rats. All the compounds were orally active in the mouse MES seizure test (ED50 values 14.5, 53.4, and 26.7 mg/kg, respectively). Moreover, 3-F-PCA was especially potent in rats, either when administered i.p. (ED50 0.4 mg/kg vs. 9.4 mg/kg in mice) or orally (ED50 0.8 mg/kg). Surprisingly, however, oral PPA failed to cause motor toxicity in mice even at doses that were many times higher than those that were protective in the MES test (TD50 greater than 300 mg/kg). In rats, 3-F-PCA also showed a strikingly low oral toxicity (TD50 greater than 50 mg/kg) in relation to its potency as an anticonvulsant. Like PCP, PCA analogues block N-methyl-D-aspartate (NMDA)-induced behavioral effects and lethality in mice. Moreover, in vitro studies indicate that the compounds act as uncompetitive antagonists of the NMDA receptor-channel complex. Therefore, their anticonvulsant activity may, at least in part, relate to an interaction with NMDA receptors.     

Bidirectional effects of beta-carbolines in reflex epilepsy

Derivatives of ethyl-beta-carboline-3-carboxylate, ZK 91296, ZK 93423 and ZK 95962 have potent anticonvulsant activity against sound-induced seizures in audiogenic DBA/2 mice and against photically-induced seizures in the baboon, Papio papio. The convulsant beta-carbolines, DMCM and beta-CCM, have proconvulsant and convulsant activity in the same animal models. DMCM and beta-CCM are similar in potency as convulsants in DBA/2 mice (ED50 value for DMCM: 1.3 mg/kg; ED50 value for beta-CCM; 0.8 mg/kg), but differ with respect to their profiles for protection by anticonvulsant drugs. The anticonvulsant potencies of diazepam and clobazam are similar against both types of beta-carboline-induced seizures, whereas quazepam protects better against beta-CCM seizures (4 fold elevation in ED50 value at 1 mg/kg quazepam IP) than against DMCM seizures (1.7 fold elevation in ED50 value), supporting a preferential action of beta-CCM on BZ1 receptors. Valproate (400 mg/kg) and gamma-vinyl-GABA (1.5 g/kg) protect better against beta-CCM seizures (9.5 and 5.9 fold elevations in ED50 values respectively) than against DMCM seizures (1.8 and 2.7 fold elevations in ED50 values respectively). The excitatory amino acid antagonist, 2-amino-7-phosphonoheptanoic acid, has significant anticonvulsant activity against DMCM seizures. The elevated regional GABA levels in brains of DBA/2 mice observed during beta-CCM seizures are eliminated by the pretreatment with Ro 15-1788, which also blocks the seizure activity.     

The anticonvulsant effects of progesterone and 5alpha-dihydroprogesterone on amygdala-kindled seizures in rats

PURPOSE: Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5alpha-dihydroprogesterone in the amygdala kindling model. METHODS: Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5alpha-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined. RESULTS: Progesterone had a median effective dose (ED50) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5alpha-dihydroprogesterone had an ED50 of 2.9 mg/kg against generalized kindled convulsions and an ED50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5alpha-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval. CONCLUSIONS: Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5alpha-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion.     

Differential Effects of Adenosine Analogs on Amygdala, Hippocampus, and Caudate Nucleus Kindled Seizures

This study explored the anticonvulsant effects of adenosine analogs at the focus of seizures kindled from various brain structures. Chemitrodes were implanted in the amygdala (AM), hippocampus (HIPP), or caudate nucleus (CN) of Long-Evans rats and electrically stimulated once daily until fully generalized seizures appeared (i.e., kindled). Once kindled, various doses (0.001-0.5 microgram/0.5 microliter) of the adenosine analogs, L-phenylisopropyladenosine (L-PIA), N-ethylcarboximidoadenosine (NECA) or vehicle were injected into the seizure focus 5 min prior to electrical stimulation. The afterdischarge (AD) and behavioral seizure stages were measured. L-PIA had potent anticonvulsant effects when injected directly into the kindled seizure focus in the AM, HIPP, or CN. NECA effects were statistically significant only in CN-kindled seizures. The regional differences in efficacy of the two adenosine analogs suggest that L-PIA, an A1 adenosine subtype agonist, may exert its effects through A1 adenosine receptors in the AM, HIPP, and CN, where A1 binding has been demonstrated, whereas NECA, an A2 adenosine receptor agonist, may only be maximally effective in the CN where A2 adenosine binding sites are located.     

Anticonvulsant activity of deaminated analogues of glutamic acid diethyl ester (GDEE)

GDEE, a specific but low-potency antagonist of the quisqualate or 'Type 2' excitatory amino acid receptor, blocks seizures induced by homocysteine and quisqualic acid. Deaminated analogues of GDEE were examined for anticonvulsant activity in mice, for the purpose of determining the structural properties of GDEE required for anticonvulsant activity. The deaminated derivative of GDEE, diethyl glutarate (5 carbon chain) inhibited homocysteine thiolactone (HTL)-induced seizures with an ED50 of 533 mg/kg. A similar compound with carbon chain length increased by two (diethyl pimelate; 7 carbons) was less effective. Decreases or further increases in carbon chain length resulted in a nearly complete loss of activity. Dimethyl glutarate (5 carbons) and dimethyl adipate (6 carbons) were similar to diethyl glutarate in potency, blocking HTL-induced seizures with ED50s of about 625 and 540 mg/kg, respectively. Diethyl ethylmalonate, diethyl maleate, and diethyl fumarate were much less effective. Diethyl glutarate, but not diethyl succinate (4 carbons), blocked seizures induced by intracerebral quisqualic acid. None of the agents tested blocked pentylenetetrazole-induced seizures. Thus a number of deaminated structural variants of GDEE have anticonvulsant activity equal to that of GDEE. The amino group of GDEE appears therefore to be irrelevant for its anticonvulsant effect.     

Dose-, time-, age-, and sex-response profiles for the anticonvulsant effects of deoxycorticosterone in 15-day-old rats

Recently, we have shown that a single high dose of the adrenal steroid precursor hormone deoxycorticosterone (DOC) has potent anticonvulsant effects in 15-day-old rats. To better define the actions of DOC, the present study established dose-, time-, age-, and sex-response curves for the anticonvulsant actions of DOC. Methods. Dose- and time-response studies were done using two different seizure models: (1) maximal pentylenetetrazol seizures (MMT) and (2) maximal electroconvulsive shock (MES) seizures. Subsequently, age- and sex-response studies were done using MMT seizures and two different DOC doses, one low (nonsedating) and one high (sedating). Results. In dose-response studies, DOC suppressed MMT seizures with an ED(50) of about 5 mg/kg (sc). Higher doses were necessary to suppress MES seizures, where the ED(50) was about 20 mg/kg. In time-response studies, DOC's effects were rapid in onset. Complete suppression of seizures was seen by 5 min in the MES model and by 15 min in the MMT model. In developmental studies, both a low nonsedating and a high sedating dose of DOC suppressed MMT seizures in neonatal, infant, weanling, and juvenile rats of either sex. The suppressive effects of low-dose DOC were lost after puberty, however. The suppressive effects of high-dose DOC also declined after puberty, especially in males. Conclusion. DOC has significant anticonvulsant actions that occur in prepubertal, but not postpubertal subjects. DOC might have clinical importance in the future treatment of childhood seizure disorders.     

Comparative Study of the Anticonvulsant Effect of γ-Aminobutyric Acid Agonists in the Feline Kindling Model of Epilepsy

We made a comparative study of the anticon-vulsant effect of GABA agonists on feline amygdala or hippocampal kindled seizures. Progabide (PGB) [γ-ami-nobutyric acid (GABA) receptor agonist 25–100 mg/kg intraperitoneally, i.p.] significantly reduced both the kindled seizure stage and after discharge (AD) duration in a dose-dependent manner. SKF89976A (GABA uptake inhibitor 0.5–2.0 mg/kg i.p.) also significantly reduced the kindled seizure stage. Toxic doses of SKF89976A caused generalized paroxysmal EEG discharges and myoclonus, but AD generation in the kindled focus was suppressed completely. Furthermore, γ-vinyl GABA (GABA cata-bolic enzyme inhibitor, GVG 50–200 mg/kg i.p.) significantly reduced the seizure stage, while causing prolongation of the AD duration. In contrast, baclofen (selective GABA_B receptor agonist, 1 or 5 mg/kg) did not show anticonvulsant effects on any parameters of kindled seizures. Therefore, these GABA agonists, which potentiate the inhibitory function of the GABA_A systems, have potent anticonvulsant effects on partial onset and secondarily generalized limbic seizures.     

Activity profile of pregabalin in rodent models of epilepsy and ataxia

Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.     

Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a potential for a second generation drug to valproic acid

Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3‐dimethylbutanoylurea (DBU), as potential second‐generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical‐, or chemical‐induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA‐induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES‐ED ₅₀ of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet‐ED ₅₀ of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED ₅₀ = 35 mg/kg), the psychomotor 6 Hz mouse model (ED ₅₀ = 80 mg/kg at 32 mA and ED ₅₀ = 133 mg/kg at 44 mA), the bicuculline‐ and picrotoxin‐induced seizure mouse model (ED ₅₀ = 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half‐life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.     

The synergistic anticonvulsant effect of agmatine and morphine: possible role of alpha 2-adrenoceptors

Recent demonstrations of the anticonvulsant properties of agmatine suggest it may be considered as a potential adjunct for protection against seizure. We investigated the possibility of an additive anticonvulsant effect between low doses of agmatine and morphine. The thresholds for the clonic seizures induced by the intravenous administration of gamma-aminobutyric acid (GABA)-antagonist, pentylenetetrazole (PTZ) were assessed in mice. Morphine at lower doses (1-3mg/kg) increased and at higher doses (30, 60 mg/kg) decreased the seizure threshold. Pretreatment with a per se non-effective dose of agmatine (1mg/kg) potentiated the anticonvulsant effect of morphine. The combination of subeffective doses of agmatine and morphine led to potent anticonvulsant effects. The pro-convulsant effect of morphine was attenuated by agmatine. Yohimbine with a dose (1mg/kg) incapable of affecting seizure threshold reversed the effect of agmatine on both anticonvulsant and pro-convulsant effects of morphine. These results suggest that agmatine potentiates the anticonvulsant effect of morphine and alpha 2-adrenoceptors may be involved in this effect.