Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation

被引：245

作者：

Ma, Lei ^{[1
]}

Seager, Matthew ^{[1
]}

Wittmann, Marion ^{[1
]}

Jacobson, Marlene ^{[5
]}

Bickel, Denise ^{[1
]}

Burno, Maryann ^{[1
]}

Jones, Keith ^{[1
]}

Graufelds, Valerie Kuzmick ^{[1
]}

Xu, Guangping ^{[1
]}

Pearson, Michelle ^{[1
]}

McCampbell, Alexander ^{[1
]}

Gaspar, Renee ^{[2
]}

Shughrue, Paul ^{[2
]}

Danziger, Andrew ^{[2
]}

Regan, Christopher ^{[2
]}

Flick, Rose ^{[5
]}

Pascarella, Danette ^{[5
]}

Garson, Susan ^{[3
]}

Doran, Scott ^{[3
]}

Kreatsoulas, Constantine ^{[4
]}

Veng, Lone ^{[2
]}

Lindsley, Craig W. ^{[4
]}

Shipe, William ^{[4
]}

Kuduk, Scott ^{[4
]}

Sur, Cyrille ^{[6
]}

Kinney, Gene ^{[2
]}

Seabrook, Guy R. ^{[1
]}

Ray, William J. ^{[1
]}

机构：

[1] Alzheimers Res, West Point, PA 19486 USA

[2] Integrat Syst Neurosci, West Point, PA 19486 USA

[3] Depress & Circadian Disorders, West Point, PA 19486 USA

[4] Med Chem, West Point, PA 19486 USA

[5] Schizophrenia Res, West Point, PA 19486 USA

[6] Imaging Merck Res Labs, West Point, PA 19486 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 37期

关键词：

PROTEIN-COUPLED RECEPTORS; SIGNAL-TRANSDUCTION; ALZHEIMERS-DISEASE; SEIZURE ACTIVITY; HIPPOCAMPUS; EXPRESSION; SUBTYPES; MICE; GENE; FEAR;

D O I：

10.1073/pnas.0900903106

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：

The forebrain cholinergic system promotes higher brain function in part by signaling through the M-1 muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M-1 receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M-1 mAChR. BQCA reduces the concentration of ACh required to activate M-1 up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 mu M. Furthermore studies in M-1(-/-) mice demonstrates that BQCA requires M-1 to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M-1 allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M-1, suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M-1 receptor and represents a promising therapeutic strategy for cognitive disorders.

引用

页码：15950 / 15955

页数：6

共 42 条

[1] Expression of disrupted-in-schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development [J].