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Allosteric modulators of α4β2 nicotinic acetylcholine receptors: a new direction for antidepressant drug discovery.

Allosteric modulation of ligand-gated ion channels has been intensively studied in the past three decades and is now an established strategy to control receptor function in numerous disease states. Allosteric sites on the GABA(A) receptor are targets for widely prescribed drugs that are used for a variety of pathophysiological states including insomnia and epilepsy. Modulators might be especially valuable to control receptors for which the design of selective orthosteric drugs has proven difficult due to safety issues (e.g., α4β2 nicotinic acetylcholine receptors and might have several advantages over orthosteric ligands. Modulators influence the action of the endogenous agonist but generally have no effect of their own on the unoccupied receptor. Moreover, the higher subtype selectivity exerted by modulators and that the effects of modulators depend on the simultaneous presence of agonist help to overcome safety problems by preventing over-dosage compared with the administration of orthosteric drugs.