Title:α-Substituted Lactams and Acetamides: Ion Channel Modulators that Show Promise in Treating Drug-resistant Epilepsy
VOLUME: 20 ISSUE: 2
Author(s):Arcadius V. Krivoshein*
Affiliation:Chemistry Program, University of Houston-Clear Lake, Houston, TX 77058
Keywords:Lactams, acetamides, antiepileptic drugs, medically refractory epilepsy, pharmacophore, neurotransmitter receptors,
ion channels.
Abstract:The two main problems in the pharmacotherapy of epilepsy are resistance to currently
available first-line medications (which occurs in about one third of patients) and the high incidence of
side effects. To address these two challenges, extensive efforts are being undertaken to design new,
structurally distinct antiepileptic drugs with a broad spectrum of anticonvulsant activity. Tests in animal
models of epilepsy indicate that α-substituted lactams and acetamides show a broad spectrum of
anticonvulsant activity (including very promising activity in drug-resistant models) as well as an excellent
safety profile. Limited clinical results confirm these preclinical findings. In the first part of this
review, pharmacology and toxicology of α-substituted lactams and acetamides and their putative protein
targets in the brain have been discussed. This is followed by a discussion of structure-activity relationships
among α-alkyl-, α-aryl-, and α-aryl-α-alkyl-substituted derivatives. The most promising
structures seem to be those related to 3-ethyl-3-phenylpyrrolidin-2-one, 2-phenylbutyramide, and 2-
sec-butylvaleramide. The information presented in this review is expected to facilitate rational drug
design and development efforts for α-substituted lactams and acetamides.
