A molecular approach to the development of anticonvulsants.
Anticonvulsants are neuronal stabilizing compounds that exhibit multiple clinical effects, including anticonvulsant, anxiolytic, sedative, and muscle-relaxant properties. This complex therapeutic picture complicates the treatment of seizure disorders in individuals with mental and developmental disorders, and frequently impairs the routine integration into society for these individuals. In order to improve the therapeutic effectiveness of these compounds, it is necessary to identify their precise molecular actions on the neuronal membrane and their effects on neuronal function. We have identified two major classes of low-affinity BZ binding sites that seem to function as generalized anticonvulsant receptors and that may mediate the anticonvulsant and sedative effects produced by these compounds. The identification of these binding sites and their anticonvulsant binding profile may clarify the complex picture of anticonvulsant mechanisms and elucidate the site(s) at which anticonvulsants produce their inhibition of MES-induced seizures and sedative effects. We will continue to examine the physiological changes induced by anticonvulsant binding at these BZ binding sites that may be a foundation for understanding the molecular basis of sedation and MES-induced seizure inhibition. Specifically, we will investigate the specific membrane components associated with the inhibition of Ca2+ channels, Na+ channel rectification, and CaM kinase II. If these goals can be achieved, then model systems could be developed to screen potential anticonvulsant or sedative compounds in the search for more effective therapeutic drugs.
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D007473:Ion Channels / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects
D000927:Anticonvulsants; D007473:Ion Channels; D011963:Receptors, GABA-A; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D002118:Calcium