title: Synthesis, anticonvulsant activity, and structure-activity relationships of sodium channel blocking 3-aminopyrroles.
abstract: 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.
authors.affiliation: Corporate Research and Development ASTA Medica Group, Arzneimittelwerk Dresden, Radebeul, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Unverferth
authors.forename: J
authors.initials: J
authors.lastname: Engel
authors.forename: N
authors.initials: N
authors.lastname: Höfgen
authors.forename: A
authors.initials: A
authors.lastname: Rostock
authors.forename: R
authors.initials: R
authors.lastname: Günther
authors.forename: H J
authors.initials: HJ
authors.lastname: Lankau
authors.forename: M
authors.initials: M
authors.lastname: Menzer
authors.forename: A
authors.initials: A
authors.lastname: Rolfs
authors.forename: J
authors.initials: J
authors.lastname: Liebscher
authors.forename: B
authors.initials: B
authors.lastname: Müller
authors.forename: H J
authors.initials: HJ
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D009498:Neurotoxins; D010433:Pentylenetetrazole; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D026941:Sodium Channel Blockers; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D007202:Indicators and Reagents; D009498:Neurotoxins; D011758:Pyrroles; D026941:Sodium Channel Blockers; D010433:Pentylenetetrazole