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

Abstract

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 α₇ nicotinic cholinergic receptor and the α₅ GABA_A receptor are emerging as attractive targets for developing therapeutics in this field. The important role of α₇ nicotinic receptors has been proven thanks to the discovery of α₇-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 α₅-containing GABA_A receptor, which seems at present the most important GABA_A receptor subtype involved in cognitive processes. This article reviews the patents on modulators of α₇ nicotinic acetylcholine and GABA_A receptors disclosed during the period 2000 – 2006.

Keywords::

• α₅ GABA_A receptors
• α₇ nicotinic acetylcholine receptors
• cognition enhancers
• nootropic compounds