Source:http://linkedlifedata.com/resource/pubmed/id/10956193
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
15
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| pubmed:dateCreated |
2000-9-5
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| pubmed:abstractText |
In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anticonvulsants,
http://linkedlifedata.com/resource/pubmed/chemical/Convulsants,
http://linkedlifedata.com/resource/pubmed/chemical/Excitatory Amino Acid Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Isoxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Kainic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Pentylenetetrazole,
http://linkedlifedata.com/resource/pubmed/chemical/Phthalazines,
http://linkedlifedata.com/resource/pubmed/chemical/Propionates,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, AMPA,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Kainic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-Amino-3-hydroxy-5-methyl-4-iso...,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-amino-3-hydroxy-5-tert-butyl-4...
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
27
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| pubmed:volume |
43
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
2851-9
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:10956193-Acoustic Stimulation,
pubmed-meshheading:10956193-Animals,
pubmed-meshheading:10956193-Anticonvulsants,
pubmed-meshheading:10956193-Cells, Cultured,
pubmed-meshheading:10956193-Convulsants,
pubmed-meshheading:10956193-Drug Evaluation, Preclinical,
pubmed-meshheading:10956193-Electroshock,
pubmed-meshheading:10956193-Excitatory Amino Acid Agonists,
pubmed-meshheading:10956193-Isoxazoles,
pubmed-meshheading:10956193-Kainic Acid,
pubmed-meshheading:10956193-Mice,
pubmed-meshheading:10956193-Mice, Inbred DBA,
pubmed-meshheading:10956193-Neurons,
pubmed-meshheading:10956193-Patch-Clamp Techniques,
pubmed-meshheading:10956193-Pentylenetetrazole,
pubmed-meshheading:10956193-Phthalazines,
pubmed-meshheading:10956193-Propionates,
pubmed-meshheading:10956193-Receptors, AMPA,
pubmed-meshheading:10956193-Receptors, Kainic Acid,
pubmed-meshheading:10956193-Seizures,
pubmed-meshheading:10956193-Structure-Activity Relationship,
pubmed-meshheading:10956193-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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| pubmed:year |
2000
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| pubmed:articleTitle |
Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones.
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| pubmed:affiliation |
Dipartimento Farmaco-Chimico and Istituto di Farmacologia, Università di Messina, Italy. grasso@pharma.unime.it
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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