Synthesis, Anticonvulsant Activity, and Structure−Activity Relationships of Sodium Channel Blocking 3-Aminopyrroles
| Autor: | Norbert Höfgen, Klaus Unverferth, Birgit Müller, Andreas Rolfs, Ralf Günther, Jürgen Liebscher, Jürgen Engel, Hans-Jörg Hofmann, Menzer Manfred, Rostock Angelika, Hans-Joachim Lankau |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Models Molecular Stereochemistry Sodium Neurotoxins chemistry.chemical_element Motor Activity Chemical synthesis Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound Sodium channel blocker Hydroxylamine Seizures Drug Discovery Animals Structure–activity relationship Pyrroles Electroshock Dose-Response Relationship Drug Molecular Structure biology Active site Rats chemistry biology.protein Pentylenetetrazole Molecular Medicine Anticonvulsants Indicators and Reagents Pharmacophore Sodium Channel Blockers Acetophenone |
| Zdroj: | Journal of Medicinal Chemistry. 41:63-73 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm970327j |
| Popis: | Starting from the corresponding acetophenone and glycine derivatives, a series of new 3-aminopyrroles was synthesized in few steps. Using this procedure with hydrazine and hydroxylamine instead of the glycinates provides access to 3-aminopyrazoles and 5-amino 1,2-oxazoles. The various derivatives were tested for anticonvulsant activity in a variety of test models. Several compounds exhibit considerable activity with a remarkable lack of neurotoxicity. 4-(4-Bromophenyl)-3-morpholinopyrrole-2-carboxylic acid methyl ester, 3, proved to be the most active compound. It was protective in the maximal electroshock seizure (MES) test in rats with an oral ED50 of 2.5 mg/kg with no neurotoxicity noted at doses up to 500 mg/kg. Compound 3 blocks sodium channels in a frequency-dependent manner. The essential structural features which could be responsible for an interaction with an active site of the voltage-dependent sodium channel are established within a suggested pharmacophore model. |
| Databáze: | OpenAIRE |
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