Activation of brain ␣7 nicotinic acetylcholine receptors (␣7 nAChRs) has broad therapeutic potential in CNS diseases related to cognitive dysfunction, including Alzheimer's disease and schizophrenia. In contrast to direct agonist activation, positive allosteric modulation of ␣7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective ␣7 nAChR-positive allosteric modulator (PAM) from a library of GABA A receptor PAMs. Compound 6 (N-(4-chlorophenyl)-␣-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at ␣7 nAChRs, while preserving the rapid native characteristics of desensitization, and has little to no efficacy at other ligand-gated ion channels. In rodent models, it corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement. Compound 6 represents a chemotype for allosteric activation of ␣7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction.cognition ͉ ion channels ͉ memory ͉ nicotine ͉ schizophrenia

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