Discovery of a selective M4 positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: Development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia

被引：37

作者：

Le, Uyen ^{[1
,3
,4
]}

Melancon, Bruce J. ^{[1
,3
,4
]}

Bridges, Thomas M. ^{[1
,3
,4
]}

Vinson, Paige N. ^{[1
,3
,4
]}

Utley, Thomas J. ^{[1
,3
,4
]}

Lamsal, Atin ^{[1
,3
,4
]}

Rodriguez, Alice L. ^{[1
,3
,4
]}

Venable, Daryl ^{[1
,3
,4
]}

Sheffler, Douglas J. ^{[1
,3
,4
]}

Jones, Carrie K. ^{[1
,3
,4
,5
]}

Blobaum, Anna L. ^{[1
,3
,4
]}

Wood, Michael R. ^{[1
,2
,3
,4
]}

Daniels, J. Scott ^{[1
,3
,4
]}

Conn, P. Jeffrey ^{[1
,3
,4
]}

Niswender, Colleen M. ^{[1
,3
,4
]}

Lindsley, Craig W. ^{[1
,2
,3
,4
]}

Hopkins, Corey R. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

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

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[4] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

[5] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37232 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 01期

关键词：

Muscarinic receptor 4; Positive allosteric modulator; Amphetamine induced hyperlocomotion; CNS; PAM; MUSCARINIC ACETYLCHOLINE-RECEPTOR; KNOCKOUT MICE; BINDING;

D O I：

10.1016/j.bmcl.2012.10.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report a next generation muscarinic receptor 4 (M-4) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC50 = 56 nM) and rat (EC50 = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：346 / 350

页数：5

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