The quest for the treatment of cognitive impairment:: α7 nicotinic and α5 GABAA receptor modulators

Age, age-related pathologies, certain psychiatric disorders, head traumas and other conditions are characterised by an impairment of cognitive functions. Cognition is a complex process involving a large number of neurotransmitters that can modulate, positively or negatively, learning and memory; therefore, their receptors may represent suitable targets to develop cognition-enhancing drugs. Among others, the alpha(7) nicotinic cholinergic receptor and the alpha(5) GABA(A) receptor are emerging as attractive targets for developing therapeutics in this field. The important role of alpha(7) nicotinic receptors has been proven thanks to the discovery Of alpha(7)-selective agonists, such as GTS-21 and AR-R17779, which has stimulated the synthesis of a large number of new compounds, some of which are in clinical trials. The observation that the classical tranquilliser benzodiazepines (agonists that potentiate GABA(A) receptor functions), are amnesic, while inverse agonists (that attenuate the functions of the same receptor) improve cognitive tasks, stimulated the search for modulators mainly directed toward the alpha(5)-containing GABA(A) receptor, which seems at present the most important GABAA receptor subtype involved in cognitive processes. This article reviews the patents on modulators of alpha(7) nicotinic acetylcholine and GABA(A) receptors disclosed during the period 2000 - 2006.