Activities of the anticonvulsant alpha-substituted lactams

Several 3,3-disubstituted 2-pyrrolidinones, 2-piperidinones, and hexahydro-2H-azepin-2-ones (five-, six- and seven-membered alpha-substituted ring lactams, respectively) exhibit potent in vivo anticonvulsant activity and relatively low toxicity. Some compare favorably to other clinically useful antiepileptic drugs. We have characterized their electrophysiological activities.; We have observed in cultured hippocampal neurons that lactams potentiate gamma-aminobutyric acid type A (GABAA) receptor-mediated currents in a reversible, concentration-dependent fashion. We also report that lactams prolong the decays of autaptic inhibitory postsynaptic currents (IPSCs). During these synaptic studies, 3-benzyl-3-ethyl-2-piperidinone (3-BEP) caused transmission failures at high concentrations, suggesting an additional presynaptic effect. We also observed that 3-BEP altered evoked action potentials. These results were consistent with effect(s) on voltage-dependent conductances. We subsequently determined that certain lactams and related drugs inhibit pharmacologically isolated Na+, K+, and Ca2+ currents.; The inhibition of voltage-dependent Na+ channels represents an important mechanism in antiepileptic pharmacology. We studied 3-BEP's effects on Na+ currents in detail. It demonstrated a voltage- and concentration-dependent inhibition. The steady-state inactivation curve was shifted toward hyperpolarized potentials, and recovery from inactivation was delayed. These effects occurred at concentrations comparable to those which potentiate GABAA currents and prolong IPSCS.; In order to study synaptic effects of lactams, we employed the "rapid application" technique with excised, outside-out patches to simulate IPSCs. Despite prolonging autaptic IPSCs, 3,3-diethyl-2-pyrrolidinone (diethyl-lactam) did not alter patch current decays. We found no evidence of a presynaptic mechanism for IPSC prolongation. Furthermore, diethyl-lactam augmented patch currents elicited by slow application of subsaturating GABA concentrations. Our findings could be explained by a contribution of subsaturating GABA concentrations to the synaptic transient underlying IPSCs.; In order to determine the diethyl-lactam concentrations required to prevent in vitro seizures and to determine whether GABAA modulation is responsible, we employed the hippocampal/entorhinal cortical slice preparation. The IC50s for seizure prevention were in excellent agreement with previously attained EC50s for GABA potentiation, and picrotoxin abolished diethyl-lactam's effects. Other derivatives with effects on voltage-dependent conductances were unable to prevent seizures in the presence of picrotoxin. These results suggest that millimolar drug levels are required and that GABA A modulation represents the major anticonvulsant mechanism of the lactams.