This is a proposal to continue a very successful and highly productive program project entitled """"""""Basic Mechanisms of Seizures"""""""". The overall goal of this program is to characterize structure-activity relationships, mechanisms and sites of action, and neurologic effects of alkyl- substituted butyrolactones and related compounds--a newly discovered class of neuroactive chemicals. Initial studies have demonstrated that these compounds can modulate the action of GABA, the major inhibitory neurotransmitter in mammalian CNS, by affecting its action at the GABA-A receptor-chloride ionophore. Several highly effective and widely used neurotropic drugs, particularly benzodiazepines and barbiturates, also act at the GABA-A receptor. This program tests the hypothesis that alkyl substituted butyrolactones have sites and mechanisms of action different from other compounds acting at the GABAA receptor-chloride ionophore and as a result of these distinct actions, these compounds have considerable potential for development as improved neurotropic therapeutic agents. The present program consists of three integrated component projects, a scientific (molecular biology) core and an administrative core. The major goals of the component projects are: 1 )To identify and synthesize new neuroactive alkyl-substituted butyrolactones and structurally related compounds and characterize their structure-activity relationships 2) To characterize the molecular sites and mechanisms of action and neurologic effects of alkyl-substituted butyrolactones and related compounds; and 3) To characterize the functional sites and mechanisms of action of alkyl- substituted butyrolactones and related compounds. These studies will utilize synthetic organic chemistry, neuropharmacology, electrophysiology, molecular biology and neuroanatomical methods and techniques. Our program brings together a group of experienced, talented and productive medical scientists who have special knowledge and research skills which make them particularly suited to carry out our goals. We have already demonstrated that we can work well together and can direct closely inter-related and complementary research projects. Our research should improve the understanding of the GABA-A receptor- chloride ionophore and other receptors in brain, help explain normal and abnormal GNS function and identify new drugs for the treatment of neurologic and psychiatric disorders including seizures and epilepsy.
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