Sleep Med 2006 May 12; (Read article online)

Bateson AN

BACKGROUND AND PURPOSE: The benzodiazepine binding site on the GABA(A) receptor is the target for the majority of hypnotics, including the nonbenzodiazepine 'Z drugs' (zaleplon, zolpidem, zopiclone and eszopiclone). Concerns still exist over long-term benzodiazepine use, and efforts are, therefore, being made to search for new hypnotic agents and alternative receptor target sites, with novel mechanisms of action. PATIENTS AND METHODS: Clinically useful compounds, including GABA mimetics and GABA-uptake inhibitors, have been found by developing structurally rigid analogs of GABA. RESULTS: The GABA-site agonist 4,5,6,7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol (THIP) shows high potency for extrasynaptic GABA(A) receptor subtypes, which are not primary targets for classical benzodiazepines or the Z drugs. Hence, THIP targets a novel set of GABA(A) receptors. The antiepileptic drug, tiagabine, is a specific blocker of the GAT-1 GABA-transporter, increasing GABA levels following synaptic GABA release. It is proposed that this promotes extrasynaptic GABA(A) receptor activity. In contrast, two other GABA analogs, pregabalin and gabapentin, are not GABA mimetics but appear to act at calcium channels responsible for neurotransmitter release, rather than at the GABA receptors. CONCLUSIONS: All of these GABA analogs modify sleep behaviors and so are potentially effective hypnotic drugs that provide an alternative to the benzodiazepine binding site of the GABA(A) receptor.