The new 2,3-benzodiazepine derivative EGIS-8332 inhibits AMPA/kainate ion channels and cell death

We observed in vitro neuroprotective and AMPA/kainate receptor antagonist effects of the new 2,3-benzodiazepine derivative EGIS-8332 ( R, S-1-(4-aminophenyl)-7,8-methylenedioxy-4-cyano-4-methyl-3- N-acetyl-5 H-3,4-dihydro-2,3-benzodiazepine) using the lactate dehydrogenase (LDH) release assay and pa...

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Published in:	Neurochemistry international Vol. 50; no. 3; pp. 555 - 563
Main Authors:	Vegh, Miklos G., Kovács, Attila D., Kovács, Gábor, Szabó, Géza, Tihanyi, Károly, Hársing, László G., Lévay, György
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-02-2007 Elsevier
Subjects:	alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology AMPA Animals Benzodiazepine Benzodiazepines - pharmacology Biological and medical sciences Cell Death - drug effects Cells, Cultured Excitatory Amino Acid Antagonists - pharmacology Fundamental and applied biological sciences. Psychology GluR1 Kainate Male Neurons - drug effects Neuroprotection NMDA Primary neuronal culture Purkinje neuron Quisqualic Acid - pharmacology Rats Rats, Wistar Receptors, AMPA - antagonists & inhibitors Receptors, Kainic Acid - antagonists & inhibitors Stereoisomerism Stereoselectivity Telencephalon - cytology Telencephalon - drug effects Vertebrates: nervous system and sense organs Stereoselectivity Neuroprotection AMPA Kainate Primary neuronal culture GluR1 Purkinje neuron Benzodiazepine NMDA Ionic channel Cell death Benzodiazepine derivatives Kainic acid
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Summary:	We observed in vitro neuroprotective and AMPA/kainate receptor antagonist effects of the new 2,3-benzodiazepine derivative EGIS-8332 ( R, S-1-(4-aminophenyl)-7,8-methylenedioxy-4-cyano-4-methyl-3- N-acetyl-5 H-3,4-dihydro-2,3-benzodiazepine) using the lactate dehydrogenase (LDH) release assay and patch clamp recordings on primary cultures of rat embryonic telencephalon neurons exposed to AMPA/kainate receptor agonists. EGIS-8332 potently decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and quisqualate induced LDH release (IC 50 = 5.2 ± 0.4 and 7.4 ± 1.3 μM, respectively) from the cells. Whole-cell patch clamp studies carried out on the ionotropic glutamate receptors N-methyl d-aspartate (NMDA), as well as AMPA (and kainate) in cultured telencephalon neurons verified that EGIS-8332 blocked steady state responses to AMPA and kainate (IC 50 = 1.7 ± 0.4 and 6.2 ± 1.6 μM, respectively), but hardly influenced currents evoked by NMDA. EGIS-8332 also inhibited kainate-evoked response in CHO cells expressing the flop variant of GluR1 receptor and, in cerebellar Purkinje cells at similar efficiency. The stereoselectivity of the inhibitory site is established by the clearly dissimilar inhibitory potency of the enantiomer components of EGIS-8332 differing in the configuration of methyl and cyano substituents on carbon C 4: the R(−) enantiomer was found to be the efficient species. This finding suggests that the inhibitory interaction between the channel protein and drug is promoted by presence of the C 4 methyl group. The inhibition of the AMPA/kainate ion channels by EGIS-8332 is non-competitive, not use dependent, and depends neither on the closed/open state of the channel, nor the membrane potential. These findings suggest an allosteric mechanism for the inhibition. These in vitro observations suggest that the compound might be useful in the treatments of certain acute and chronic neurological syndromes initiated by derangements of ionotropic glutamate receptor function.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0197-0186 1872-9754
DOI:	10.1016/j.neuint.2006.11.003