Medicinal Chemistry and Drug Design

Biography

Biography: Karol S. Bruzik

Abstract

Heteropentameric GABA-A receptor is a principal drug target whose function is allosterically modulated by general anesthetics, sedatives and anticonvulsants, such as propofol, etomidate, barbiturates and neurosteroids. The current clinically used general anesthetics have numerous disadvantages including low potency, low receptor-type selectivity among the various Cys-loop receptors, low receptor isoform selectivity and resulting therefrom low therapeutic indices. Determining the locations and structures of modulator sites and the mechanisms that trigger conformational changes to the receptor is essential to the design and development of the next generation of these drugs.  The approach presented here garners this information using chemical synthesis of analogs of the general anesthetic drugs equipped with small photoactivatable residues such as a diazirine or an azide, characterization of the pharmacology of the new agents to verify the identity of their binding sites with those of the original drugs, photolabeling of a specific molecular isoform of the receptor, and performing Edman sequencing of the photolabeled fragments of the receptor to determine the position of modification.  Using this approach, binding sites of barbiturates (1), propofol (2), etomidate (3), and neurosteroids (4-8) have been determined.  This presentation will focus on various synthetic approaches to the general anesthetic analogs (shown), the effect that small structural changes have to ligands’ binding sites and the pharmacological activities, and the use of the ligands in protein photolabeling and identification of the photolabeled sites. Overall, a general picture emerges where agents belonging to the four different classes mentioned above bind to disparate regions of the receptor protein.