Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators

被引：158

作者：

Ng, Herman J.

Whittemore, Edward R.

Tran, Minhtam B.

Hogenkamp, Derk J.

Broide, Ron S.

Johnstone, Timothy B.

Zheng, Lijun

Stevens, Karen E.

Gee, Kelvin W. ^{[1
]}

机构：

[1] Univ Calif Irvine, Sch Med, Dept Pharmacol, Irvine, CA 92697 USA

[2] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 19期

关键词：

cognition; ion channels; memory nicotine; schizophrenia;

D O I：

10.1073/pnas.0701321104

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Activation of brain alpha 7 nicotinic acetylcholine receptors (alpha 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 alpha 7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective a7 nAChR-positive allosteric modulator (PAM) from a library of GABAA receptor PAMs. Compound 6 (N-(4-chlorophenyl)-alpha-[[(4-chlorophenyl)aminolmethylenel-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at alpha 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 alpha 7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction.

引用

页码：8059 / 8064

页数：6