Ligands for the benzodiazepine binding site - a survey

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian Central Nervous System (CNS). GABA participates in the regula tion of neuronal excitability through interaction with specific membrane pr oteins (thr GABA(A) receptors). The binding of GABA to these postsynaptic r eceptors, results in an opening of a chloride channel integrated in the rec eptor which allows the entry of Cl- and consequently leads to hyperpolariza tion of the recipient cell. The action of GABA is allosterically modulated by a wide variety of chemical entities which interact with distinct binding sites at the GABA(A) receptor complex. One of the most thoroughly investig ated modulatory site is;the benzodiazepine binding site. The benzodiazepine s constitute a well-known class of therapeutics displaying hypnotic, anxiol ytic and anticonvulsant effects. Their usefulness, however, is limited by a broad range of side effects comprising sedation, ataxia, amnesia, alcohol and barbiturate potentiation, tolerance development and abuse potential. Co nsequently, there has been an intensive search for modulatory agents with a n improved profile, and a diversity of chemical entities distinct from the benzodiazepines, but with GABA modulatory effects have been identified. The existence of endogenous ligands for the GABA(A) receptor complex beside GA BA has often been described, but their role in the regulation of GABA actio n is still a matter of controversy. The progress of molecular biology durin g the last decade has contributed enormously to the understanding of benzod iazepine receptor pharmacology. A total of 14 GABA(A) receptor subunits hav e been cloned from mammalian brain and have been expressed/co-expressed in stable: cell lines. These transfected cells constitute an important tool in the characterization of subtype selective ligands. In spite of the rapidly expanding knowledge of the molecular and pharmacological mechanisms involv ed in GABA/benzodiazepine related CNS disorders, the identification of clin ically selective acting drugs is still to come.