cfm-2 and Seizures

In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice, and the 1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl) derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA receptor modulator.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; In Vitro Techniques; Isoquinolines; Male; Mice; Mice, Inbred DBA; Olfactory Pathways; Piperidines; Rats; Rats, Wistar; Receptors, AMPA; Seizures; Structure-Activity Relationship; Tetrahydroisoquinolines

As a follow up of our previous structure-activity relationship and molecular modeling studies, we synthesized a novel series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these novel compounds showed high anticonvulsant potency.

Topics: Animals; Anticonvulsants; Benzodiazepines; Benzodiazepinones; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Female; Male; Mice; Mice, Inbred DBA; Models, Molecular; Molecular Structure; Receptors, AMPA; Seizures; Structure-Activity Relationship; Tetrahydroisoquinolines

N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Excitatory Amino Acid Antagonists; Isoquinolines; Ligands; Mice; Mice, Inbred DBA; Receptors, AMPA; Seizures; Structure-Activity Relationship; Tetrahydroisoquinolines

We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e. enhanced the anticonvulsant properties) of 1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one hydrochloride, CFM-2, a noncompetitive AMPA receptor antagonist, and 3-((+/-)-2-carboxypiperazin-4-yl)-1-phosphonic acid, CPPene, a competitive NMDA receptor antagonist, in DBA/2 mice. In addition, (R,S)-PPG and ACPT-1 administered intracerebroventricularly prolonged the time course of the anticonvulsant properties of CFM-2 (33 micromol/kg, i.p.) and CPPene (3.3 micromol/kg, i.p.) administered intraperitoneally. We conclude that modest reduction of synaptic glutamate release by activation of Group III metabotropic receptors potentiates the anticonvulsant effect of AMPA and NMDA receptor blockade.

Topics: Animals; Anticonvulsants; Benzodiazepinones; Cyclopentanes; Drug Synergism; Female; Injections, Intraventricular; Male; Mice; Mice, Inbred DBA; Motor Activity; Receptors, Metabotropic Glutamate; Seizures; Tricarboxylic Acids

A series of 2,3-benzodiazepine derivatives has been previously described as noncompetitive AMPA-type glutamate receptor antagonists potentially useful for treatment of epilepsy. To further explore the structure-activity relationships of AMPA antagonists, a series of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) was synthesized starting from the corresponding bicyclic 1-aryl-3, 5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. In addition, they antagonize the AMPA-induced seizures, and their anticonvulsant activity is reversed by pretreatment with aniracetam, thus suggesting the involvement of AMPA receptors. The pharmacological studies revealed that the 11H-[1,2,4]triazolo[4, 5-c][2,3]benzodiazepin-3(2H)-ones (6) herein reported show anticonvulsant activity comparable to that of their bicyclic precursors. Furthermore, an HPLC study put in evidence that these tricyclic derivatives 6 were converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.

Topics: Acoustic Stimulation; Allosteric Regulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Benzodiazepines; Chromatography, High Pressure Liquid; Electroshock; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred DBA; Motor Activity; Pentylenetetrazole; Pyrrolidinones; Receptors, AMPA; Seizures; Structure-Activity Relationship

A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2, 3-benzodiazepin-4-one (6), which had an IC50 of 2.7 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.

Topics: Allosteric Regulation; Animals; Anti-Anxiety Agents; Anticonvulsants; Azepines; Benzodiazepines; Cerebral Cortex; Electroshock; Excitatory Amino Acid Antagonists; Male; Membrane Potentials; Mice; Oocytes; Rats; Receptors, AMPA; RNA, Messenger; Seizures; Xenopus laevis

Synthesis and evaluation of anticonvulsant activity of a series of 2,3-benzodiazepin-4-ones (2) chemically related to 1-(4'-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant properties acting as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. In an attempt to better define the structure-activity relationships (SAR) and to obtain more potent and selective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2, 3-benzodiazepine-4-thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the audiogenic seizures test with DBA/2 mice and against the maximal electroshock- and pentylenetetrazole-induced seizures in Swiss mice. New derivatives 3 showed higher potency, less toxicity and longer-lasting anticonvulsant action than those of the parent compounds 2 in all tests employed. Analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced seizures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involvement of AMPA receptors. Electrophysiological data indicate a noncompetitive blocking mechanism at the AMPA receptor sites for 3i, the most active of the series and over 5-fold more potent than 1.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Benzodiazepines; Convulsants; Electroshock; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Guinea Pigs; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; Motor Activity; Olfactory Pathways; Patch-Clamp Techniques; Pentylenetetrazole; Pyrrolidinones; Rats; Receptors, AMPA; Seizures; Structure-Activity Relationship; Thiones

The synthesis and anticonvulsant activity of novel 7,8-methylenedioxy-4H-2,3-benzodiazepin-4-ones 3a-e, structurally-related to GYKI 52466 1, a well-known noncompetitive AMPA-receptor antagonist, are reported. The new compounds possess marked anticonvulsant properties and, in analogy to 1, antagonize seizures induced by AMPA. In addition, when compared to the model compound 1, compounds 3 show a longer-lasting anticonvulsant activity and a lower toxicity.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Benzodiazepinones; Excitatory Amino Acid Antagonists; Indicators and Reagents; Mice; Mice, Inbred DBA; Molecular Structure; Motor Activity; Receptors, AMPA; Seizures; Structure-Activity Relationship

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. 1-(4'-Aminophenyl)- (38) and 1-(3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin- 4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED50 values against tonus evoked by auditory stimulation were 12.6 micromol/kg for derivative 38, 18.3 micromol/kg for 39, and 25.3 micromol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [3H]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Benzodiazepinones; Convulsants; Mice; Mice, Inbred DBA; Pentylenetetrazole; Pyrrolidinones; Receptors, AMPA; Seizures