Evaluation of Anticonvulsant Actions of Dibromophenyl Enaminones Using In Vitro and In Vivo Seizure Models (original) (raw)
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Neuroscience, 2006
Enaminones are a novel group of compounds some of which possess anticonvulsant activity in in vivo animal models of seizures. We recently reported that some enaminones, including methyl 4-(4=-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate, depress glutamate-mediated excitatory synaptic transmission and that this may contribute to their anticonvulsant activity [Kombian SB, Edafiogho IO, Ananthalakshmi KVV (2005) Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels. Br J Pharmacol 145:945-953]. Here we studied the effects of methyl 4-(4=-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate, on the excitability of male rat (Sprague-Dawley) nucleus accumbens and hippocampal cells in vitro using whole-cell patch clamp recording techniques. At low, therapeutically relevant concentrations (0.3-10 M), methyl 4-(4=-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate reversibly suppressed action potential firing rate in a concentration-dependent manner. This action potential suppression was present when GABA A , GABA B and glutamate receptors were blocked with their antagonists. Furthermore, methyl 4-(4=-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate suppressed tetrodotoxin-sensitive sodium currents in these cells. At concentrations >100 M, it induced inward currents and increased action potential firing frequency. The inward currents were without changes in input resistance and did not reverse polarity between ؊120 and ؊40 mV. These currents were independent of extracellular potassium, but were absent when extracellular sodium was replaced by choline and finally, were occluded by pretreatment with ouabain (200 M). We conclude that methyl 4-(4=-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate directly inhibits action potential firing at therapeutically relevant concentrations by suppressing tetrodotoxin-sensitive sodium currents, while inducing an ouabain-sensitive current at high concentrations to excite neurons. These two actions of methyl 4-(4=-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate on neuronal excitability would have therapeutic implications in future clinical use of enaminones as anticonvulsants in seizure disorders.
6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity
International Journal of Environmental Research and Public Health
A small library of novel fluorinated N-benzamide enaminones were synthesized and evaluated in a battery of acute preclinical seizure models. Three compounds (GSA 62, TTA 35, and WWB 67) were found to have good anticonvulsant activity in the 6-Hz ‘psychomotor’ 44-mA rodent model. The focus of this study was to elucidate the active analogs’ mode of action on seizure-related molecular targets. Electrophysiology studies were employed to evaluate the compounds’ ability to inhibit neuronal activity in central olfactory neurons, mitral cells, and sensory-like ND7/23 cells, which express an assortment of voltage and ligand-gated ion channels. We did not find any significant effects of the three compounds on action potential generation in mitral cells. The treatment of ND7/23 cells with 50 µM of GSA 62, TTA 35, and WWB 67 generated a significant reduction in the amplitude of whole-cell sodium currents. Similar treatment of ND7/23 cells with these compounds had no effect on T-type calcium cur...
British Journal of Pharmacology, 1997
1 Earlier optimization of structure-activity relationships in a novel series of 4-(benzoylamino)benzopyrans, led to the discovery of SB-204269 (trans-(+)-6-acetyl-4S-(4-¯uorobenzoylamino)-3,4dihydro-2,2-dimethyl-2H-benzo [b]pyran-3R-ol, hemihydrate), a potent orally-active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test. 2 Studies have now been undertaken to determine the eects of SB-204269 in a range of seizure models and tests of neurological de®cits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays. 3 SB-204269 proved to be an orally-eective anticonvulsant agent, at doses (0.1 ± 30 mg kg 71 ) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MES)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)-evoked tonic extension seizures. However, the compound did not inhibit PTZ-induced myoclonic seizures at doses up to 30 mg kg 71 , p.o. 4 SB-204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K + rat hippocampal slice model at concentrations (0.1 ± 10 mM) that had no eect on normal synaptic activity and neuronal excitability. 5 In all of these seizure models, SB-204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and ecacy. 6 Unlike SB-204269, the corresponding trans 3S,4R enantiomer, SB-204268, did not produce marked anticonvulsant eects, an observation in accord with previous ®ndings for other related pairs of trans enantiomers in the benzopyran series. 7 In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological de®cits such as sedation and motor incoordination, SB-204269 was inactive even at doses as high as 200 mg kg 71 , p.o. This was re¯ected in the excellent therapeutic index (minimum signi®cantly eective dose in the rotarod test/ED 50 in the MES test) for SB-204269 of 431, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively. 8 At concentrations (510 mM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 mM in brain), SB-204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na + channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB-204269 are likely to be mediated by a novel stereospeci®c binding site present in the CNS. 9 The overall ecacy pro®le in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB-204269 for the treatment of refractory partial and generalized tonic-clonic seizures.
European Journal of Pharmacology, 1995
1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466), up to 5 mg/kg, did not influence the electroconvulsive threshold but potentiated the anticonvulsant activity of valproate, carbamazepine and diphenylhydantoin against maximal electroshock-induced convulsions in mice. No potentiation was observed in the case of phenobarbital. Moreover, this non-NMDA receptor antagonist did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction, in terms of total and free plasma levels, is not probable. The combined treatment of GYKI 52466 with either carbamazepine or diphenylhydantoin (providing a 50% protection against maximal electroshock) was devoid of significant side effects (motor and long-term memory impairment). Valproate applied at a dose equal to its EDs0 caused serious worsening of motor coordination and long-term memory. It is noteworthy that the combined treatment of GYKI 52466 with valproate was superior to valproate alone, as regards adverse effects. The results suggest that concomitant administration of GYKI 52466 with some conventional antiepileptic drugs may offer a novel approach in the treatment of epilepsy.
The GABA withdrawal syndrome (GWS) is a new model of focal epilepsy in which paroxysmal activity is induced through the interruption of a chronic, intracortical infusion of GABA. Preliminary studies have shown extraordinary resistance of this epileptogenic activity to classic anticonvulsants including diazepam, the most effective agent for treating status epilepticus. However, GWS can be inhibited by GABA itself. The rat with petit mal-like seizures is a genetic model of generalized non-convulsive epilepsy (GNCE), with behavioral characteristics and electrical (spike-and-wave discharges) signs resembling absences. Moreover, GABAmimetics aggravate this type of seizure. Rats with GWS induced by cessation of a localized GABA infusion (50 μg/μ1/h for 24 h), and the rat model of GNCE, were treated with HEPP, a new anticonvulsant agent. In the case of GWS, the drug produced a significant decrease of focal spike activity in animals which started discharging at low frequencies while in rats with higher frequency discharge, HEPP was without effect. HEPP administered on the second day of the GWS in naive rats had no effect. In rats with GNCE, doses of 50 and 100 mg/kg i.p. blocked the spike-and-wave discharges. The higher dose produced sedation in this absence seizures model. Although the mechanism of action of HEPP is still unknown, its unique antiepileptic profile deserves further studies.
Molecules, 2021
C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed ...
Bioorganic & Medicinal Chemistry, 1999
A new series of N-modified analogues of the VV-hemorphin-5 with aminophosphonate moiety have been synthesized, characterized and investigated for anticonvulsant activity. The novel peptide analogues were prepared by solid-phase peptide synthesis-Fmoc-strategy and were evaluated in the timed intravenous pentylenetetrazole infusion test (ivPTZ) and 6-Hz psychomotor seizure test in mice. The acute neurological toxicity was determined using the rotarod test. The redox potentials at glass carbonic electrode (GC) and the acid/base properties as pKa values of these peptide analogues were compared with the electrochemical behaviour of tyrosine-and tryptophan-containing peptides using different voltamperometric modes. Among the five tested peptide analogues, V3p was the most active against the ivPTZ test with effect comparable to that of the VV-hemorphin-5 (V1) used as a positive control. Dose-dependent elevation of the seizure threshold for myoclonic twitch and generalized clonic seizures was observed after i.c.v. administration of V2p, V4p and V5p as well as for forelimbs tonus in V4p peptides. The peptide analogues V2p-V5p were able to suppress dose-dependent psychomotor seizures in the 6-Hz test. In contrast, the V6p peptide showed either a pro-convulsant effect in the iv PTZ test or was inactive in the 6-Hz test. No changes in motor coordination were noted with the novel peptides. Docking study results suggest that kappa opioid receptor binding could be the mechanism of action of peptide derivatives with anticonvulsant activity. The results suggest that incorporation of aminophosphonate moiety at position 1 of the VV-hemorphin-5 scaffold deserve further evaluation in models of epilepsy and derivatization.