The overall goal of this proposed interdisciplinary effort is the computer-aided design of new therapeutic agents with improved pharmacological profiles which exert their effect by binding to the BDZ/GABA(A) receptor (BDZ ligands). To this end, we have used the techniques o f theoretical chemistry to identify and characterize reliable molecular determinants of receptor recognition and types of activity, i,e., agonism, antagonism, and inverse agonim. We have used these steric and electronic properties as criteria for the identification of known compounds and the design of new ones to be synthesized which could be BDZ ligands with desired activity such as antagonists with improved pharmacokinetic characteristics, medium efficacy agonists which may have less side effects such as sedation, potentiation of ethanol, tolerance and physical dependence, and inverse agonists which may be useful therapeutic agents in themselves. These analogs will be characterized theoretically and subjected to diverse pharmacological evaluations including receptor binding, in vitro physiological studies and a spectrum of in vivo behavioral endpoints. Iterative interaction between the results of theoretical and expeerimental studies will be used throughout this work to design several generations of continuously improved analogs. In a parallel effort, we plan to continue interdisciplinary effort to further understand the mechanisms of the various biological activities of the BDZ ligands and to test, refine and expand our existing criteria for recognition and activation. To this end, new families of BDZ ligands will be studied, new behavioral and physiological end points used, and receptor heterogeneity explored. In a third related effort, we plan to use computer-assisted techniques to explicitly characterize and develop a structure for the BDZ binding site in the alpha-subunit of the GABA receptor. These procedures will involve identification of key amino acids in the binding site, secondary structure algorithms, a systematic search of a data base of proteins with known X-ray structure and energy optimization procedures. Taken together, the results of this multidisciplinary, mulifaceted study should lead to both optimally designed new BDZ ligands and to further understanding of their mechanisms of action.
Showing the most recent 10 out of 18 publications
