MOLECULAR MODELING, DESIGN AND EVALUATION OF BDZ LIGANDS

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The overall goal of this proposed interdisciplinary effort continues to be the computer assisted design of new therapeutic agents with improved pharmacological profiles, which exert their effects by binding to the BDZ/GABA-A receptor (BDZR ligands). To this end, we shall continue to 1) validate current hypotheses for non selective ligands involving common molecular determinants of recognition of BDZ/GABA-A receptor(s) and determinants of activation based on their anticonvulsant endpoint and identify promising medications designed using them. This goal will be accomplished by: a) Continued theoretical characterization of additional families of compounds reported in the literature that were not included in the original data set for hypothesis development, and b) synthesis and pharmacological evaluation of two of the families with predicted pharmacological profiles originally proposed based on this hypothesis: i) azaindoles; ii) pyrroloquinolines. 2) Enhance knowledge of BDZ in vitro and in vivo pharmacology in light of emerging developments in molecular biology, in a manner that will also result in an appropriate database for hypothesis refinement and design of second generation analogs. To accomplish this aim we shall: a) Synthesize analogs of compounds that have been reported to have interesting pharmacological profiles that could be useful to i) probe receptor heterogeneity because of their ability to bind selectively or ii) elicit qualitatively different responses i.e. agonism, antagonism, inverse agonism or no response in different behavioral endpoints, b) Continue to characterize receptor heterogeneity, addressing the question of the number of central BDZR subtypes using different brain regions reported to have limited subtype heterogeneity and using additional ligands; c) Explore the usefulness of chloride ion flux as an indication of agonist, antagonist and inverse agonist activity in each brain region used for receptor binding studies; d) Use the six in vivo endpoints: anxiolytic, anticonvulsant, hyperphagia, sedation, muscle relaxant and hypothermia, to characterize additional known families and the newly synthesized ones, found to bind with significant affinity to any BDZ/GABA-A receptor subtype. The goal of these studies is to determine promising differences in the ability of a set of chosen compounds to differentially elicit these activities. These results will be useful for two different purposes: i) to serve as a database for the design of activity-specific analogs and ii) to further elucidate the relationship between recognition of a given subtype and in vivo responses. 3.Use the techniques of theoretical chemistry for the same compounds to be studied experimentally, in an "interim" design strategy based on molecular determinants of activation at each in vivo endpoint. Implicit in this approach is the determination of common properties modulating recognition of all receptors involved in the particular endpoint considered. This strategy will lead to refinements of our current hypotheses that will be used to design activity-selective compounds that could be more targeted medications.