Benzodiazepines

Abstract

Starting with a short overview on the pharmacology of Benzodiazepine (BZ) receptor ligands that includes aspects of their therapeutic actions, development of tolerance and dependence to BZ and their metabolism this review pays special attention to the interaction and mode of action of BZ with the various γ‐aminobutyric acid type A (GABA A ) receptors. We discuss the diversity of GABA A receptors with respect to the subunits, receptor subtypes, brain distribution and function. The functional domains on GABA A receptors needed for the recognition and action of GABA and BZ as well as those needed for assembly are described. The structure activity relations of benzodiazepines are discussed with an emphasis on GABA A receptor subtypes.

Anxioselective anxiolytics: on a quest for the Holy Grail

“…However, an α1, 2, 3, or 5 subunit and a γ subunit are required for high affinity binding of 1,4-BZs (and the other structurally distinct molecules discussed in this review) 1 . Hence, GABA A receptors containing an α 1,2,3, or 5 subunit have been referred to as “diazepam-sensitive” (DS), whereas receptor isoforms bearing an α 4 or α 6 subunit are referred to as “diazepam-insensitive” (DI) [8]. …”

“…Subsequent studies have demonstrated that multiple amino acid residues on both the α and γ subunits can influence both the potency and efficacy of these molecules [8]. However, the ability to dramatically reduce the affinity of BZs by this His→Arg mutation was critical for a second wave of efforts to develop anxioselective agents.…”

“…The commercial interest in developing anxioselectives, together with a technology enabling the interrogation of large numbers of molecules [10, 11] and advances in the molecular biology of GABA A receptors [7,8, 28], resulted in the identification of more than a dozen molecules (Figure 1) [7,8, 29] with preclinical profiles consistent with anxioselectivity. A subset of these compounds was developed further, and the clinical effects of at least eight molecules have been reported in peer-reviewed journals.…”

“…The molecular and structural requirements for high affinity ligand binding at recombinant GABA A receptors are well understood [8,9]. …”