The objective of the research proposed herein is to develop subtype- selective ligands for the GABA/A -benzodiazepine receptors (BzRs) of the central nervous system. Recently there has been a growing interest in investigating the physiological role and function of a subtype of benzodiazepine receptors referred to as the diazepam-insensitive (DI) BzR. The DI receptors have a pharmacological profile and neuroanatomical distribution which is distinct from other diazepam sensitive (DS) BzR subtypes. All of the high-affinity DI ligands that are currently available also bind with high affinity to the DS GABA/A receptors. This lack of selective ligands for the DI site has been a severe constraint on biological studies aimed at the characterization of the pharmacological function of this subtype of benzodiazepine receptOrs. Recent studies in our laboratories on a group of compounds that are related to the imidazobenzodiazepinone drugs Flumazenil and Ro 15-4513, have revealed that the affinity and selectivity of the imidazo(1,5alpha][1,4] benzodiazepin-6-ones to the DI and DS receptors can be modulated by structural manipulations involving the placement of suitable substituents at the 3-, 5- and -positions of the basic template. The research proposed herein seeks to utilize the knowledge gained from these structure-activity relationship (SAR) and computer-assisted modelling studies in the design and development of newer ligands that might possess enhanced affinity and selectivity for the DI site. New target ligands to be synthesized will be evaluated to determine their affinity and selectivity profile and to determine the DI receptor mediated pharmacological and behavioral effects in mice and in an avian model. The biological evaluations will be carried out in collaboration with Dr. Phil Skolnick at the Laboratory of Neuroscience, NIDDK, NIH and Dr. Jeffrey Witkin at the Laboratory of Psychobiology, Addiction Research Center, NIDA. These studies involving the synthesis and biological evaluations should provide a greater understanding of the factors governing ligand-selectivity to the BzR subtypes and should potentially lead to the discovery and development of sub-type selective drugs for the DI-GABA/A receptors.
