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Nootropic α7 nicotinic receptor allosteric modulator derived from GABA A receptor modulators

2007; National Academy of Sciences; Volume: 104; Issue: 19 Linguagem: Inglês

10.1073/pnas.0701321104

1091-6490

Herman Jalli Ng, Edward R. Whittemore, Minhtam Tran, Derk J. Hogenkamp, Ron S. Broide, Timothy Johnstone, Lijun Zheng, Karen E. Stevens, Kelvin W. Gee,

Receptor Mechanisms and Signaling

Activation of brain α7 nicotinic acetylcholine receptors (α7 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 α7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective α7 nAChR-positive allosteric modulator (PAM) from a library of GABA A receptor PAMs. Compound 6 ( N -(4-chlorophenyl)-α-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at α7 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 α7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction.