Synthesis and Structure-Activity Relationships of Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor

被引：40

作者：

Kennedy, J. Phillip ^{[1
]}

Bridges, Thomas M. ^{[2
]}

Gentry, Patrick R. ^{[2
]}

Brogan, John T. ^{[1
]}

Kane, Alexander S. ^{[2
]}

Jones, Carrie K. ^{[2
,3
]}

Brady, Ashley E. ^{[2
]}

Shirey, Jana K. ^{[2
]}

Conn, P. Jeffrey ^{[2
]}

Lindsley, Craig W. ^{[1
,2
]}

机构：

[1] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Vanderbilt Program Drug Discovery, Dept Pharmacol, Med Ctr, Nashville, TN 37232 USA

[3] TVHS, US Dept Vet Affairs, Nashville, TN 37212 USA

来源：

CHEMMEDCHEM | 2009年 / 4卷 / 10期

关键词：

allosteric; muscarinic; potentiators; receptors; schizophrenia; structure-activity relationships; HISTAMINE H-3 RECEPTOR; KNOCKOUT MICE; ANTAGONISTS; DISORDERS; SYSTEM; GENES; RATS;

D O I：

10.1002/cmdc.200900231

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

(Chemical Equation Presented) An iterative analogue library synthesis strategy rapidly developed comprehensive SAR data for a novel series of M 4 positive allosteric modulators (PAMs). This effort identified key moieties that improved microsomal stability and physiochemical properties. Moreover, this series displayed an order of magnitude greater potency for human versus rat M4, providing compounds with EC50 values in the 100 nM range. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

引用

页码：1600 / 1607

页数：8

共 21 条

[1]

Abu-Shanab F.A., 2006, J SULPHUR CHEM, V27, P293

[2] IDENTIFICATION OF A FAMILY OF MUSCARINIC ACETYLCHOLINE-RECEPTOR GENES [J].

BONNER, TI ;

BUCKLEY, NJ ;

YOUNG, AC ;

BRANN, MR .

SCIENCE, 1987, 237 (4814) :527-532

[3] CLONING AND EXPRESSION OF THE HUMAN AND RAT M5 MUSCARINIC ACETYLCHOLINE-RECEPTOR GENES [J].

BONNER, TI ;

YOUNG, AC ;

BRANN, MR ;

BUCKLEY, NJ .

NEURON, 1988, 1 (05) :403-410

[4] Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats [J].

Brady, Ashley E. ;

Jones, Carrie K. ;

Bridges, Thomas M. ;

Kennedy, J. Phillip ;

Thompson, Analisa D. ;

Heiman, Justin U. ;

Breininger, Micah L. ;

Gentry, Patrick R. ;

Yin, Huiyong ;

Jadhav, Satyawan B. ;

Shirey, Jana K. ;

Conn, P. Jeffrey ;

Lindsley, Craig W. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 327 (03) :941-953

[5] G-protein-coupled receptors: From classical modes of modulation to allosteric mechanisms [J].

Bridges, Thomas M. ;

Lindsley, Craig W. .

ACS CHEMICAL BIOLOGY, 2008, 3 (09) :530-541

[6] Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system [J].

Bymaster, FP ;

McKinzie, DL ;

Felder, CC ;

Wess, J .

NEUROCHEMICAL RESEARCH, 2003, 28 (3-4) :437-442

[7] MUSCARINIC RECEPTORS - CHARACTERIZATION, COUPLING AND FUNCTION [J].

CAULFIELD, MP .

PHARMACOLOGY & THERAPEUTICS, 1993, 58 (03) :319-379

[8] Histamine H3 receptor antagonists reach out for the clinic [J].

Celanire, S ;

Wijtmans, M ;

Talaga, P ;

Leurs, R ;

de Esch, IJP .

DRUG DISCOVERY TODAY, 2005, 10 (23-24) :1613-1627

[9] Muscarinic receptor agonists and antagonists in the treatment of Alzheimer's Disease [J].

Clader, JW ;

Wang, YG .

CURRENT PHARMACEUTICAL DESIGN, 2005, 11 (26) :3353-3361

[10] Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders [J].

Conn, P. Jeffrey ;

Christopoulos, Arthur ;

Lindsley, Craig W. .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (01) :41-54

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