Identification of N-substituted 8-azatetrahydroquinolone derivatives as selective and orally active M1 and M4 muscarinic acetylcholine receptors agonists

被引：9

作者：

Takai, Kentaro ^{[1
]}

Inoue, Yasunao ^{[1
]}

Konishi, Yasuko ^{[1
]}

Suwa, Atsushi ^{[1
]}

Uruno, Yoshiharu ^{[1
]}

Matsuda, Harumi ^{[1
]}

Nakako, Tomokazu ^{[1
]}

Sakai, Mutsuko ^{[1
]}

Nishikawa, Hiroyuki ^{[1
]}

Hashimoto, Gakuji ^{[1
]}

Enomoto, Takeshi ^{[1
]}

Kitamura, Atsushi ^{[1
]}

Uematsu, Yasuaki ^{[1
]}

Kiyoshi, Akihiko ^{[1
]}

Sumiyoshi, Takaaki ^{[1
]}

机构：

[1] Dainippon Sumitomo Pharma Co Ltd, Drug Res Div, Suita, Osaka, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 16期

关键词：

M-1 muscarinic acetylcholine receptor; M-4 muscarinic acetylcholine receptor; Selective agonist; Schizophrenia; Antipsychotic agents; 8-Azatetrahydroquinolone; XANOMELINE; SCHIZOPHRENIA; PHARMACOLOGY; SYMPTOMS; MICE;

D O I：

10.1016/j.bmcl.2013.06.013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M-1 and M-4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4644 / 4647

页数：4

共 24 条

[21] N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity [J].

Sur, C ;

Mallorga, PJ ;

Wittmann, M ;

Jacobson, MA ;

Pascarella, D ;

Williams, JB ;

Brandish, PE ;

Pettibone, DJ ;

Scolnick, EM ;

Conn, PJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (23) :13674-13679

[22] Targeting Selective Activation of M1 for the Treatment of Alzheimer's Disease: Further Chemical Optimization and Pharmacological Characterization of the M1 Positive Allosteric Modulator ML169 [J].

Tarr, James C. ;

Turlington, Mark L. ;

Reid, Paul R. ;

Utley, Thomas J. ;

Sheffler, Douglas J. ;

Cho, Hyekyung P. ;

Klar, Rebecca ;

Pancani, Tristano ;

Klein, Michael T. ;

Bridges, Thomas M. ;

Morrison, Ryan D. ;

Blobaum, Anna L. ;

Xiang, Zixui ;

Daniels, J. Scott ;

Niswender, Colleen M. ;

Conn, P. Jeffrey ;

Wood, Michael R. ;

Lindsley, Craig W. .

ACS CHEMICAL NEUROSCIENCE, 2012, 3 (11) :884-895

[23] Probe Dependence in the Allosteric Modulation of a G Protein-Coupled Receptor: Implications for Detection and Validation of Allosteric Ligand Effects [J].

Valant, Celine ;

Felder, Christian C. ;

Sexton, Patrick M. ;

Christopoulos, Arthur .

MOLECULAR PHARMACOLOGY, 2012, 81 (01) :41-52

[24] Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice [J].

Woolley, Marie L. ;

Carter, Helen J. ;

Gartlon, Jane E. ;

Watson, Jeanette M. ;

Dawson, Lee A. .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2009, 603 (1-3) :147-149

← 1 2 3 →