Bioorganic & Medicinal Chemistry Letters 2009-09-01

In vivo evaluation of diaminodiphenyls: anticonvulsant agents with minimal acute neurotoxicity.

David R Worthen, Aimee K Bence, James P Stables, Peter A Crooks

Index: Bioorg. Med. Chem. Lett. 19 , 5012-5, (2009)

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Abstract

Several diaminodiphenyl analogs were assessed in vivo for their capacity to inhibit seizure induction and propagation in rodents. Both 3,4'- and 4,4'-diaminodiphenyl compounds prevented seizures for as long as 4h after maximal electric shock induction. 4,4'-Diphenyl compounds bridged by a methylene, sulfide, or carbonyl linker also attenuated focal seizure acquisition in a kindling model. Of these analogs, based upon data generated in two rodent species, 4,4'-thiodianiline (1) was identified as the most active compound, significantly reducing seizure staging scores and after-discharge duration for several hours after systemic administration. All compounds were devoid of acute in vivo neurotoxicity at doses well above those required for anticonvulsant activity.