Synthesis and biological evaluation of isoxazoline derivatives as potent M1 muscarinic acetylcholine receptor agonists

被引：11

作者：

Huang, Minghua ^{[1
,3
]}

Suk, Dae-Hwan ^{[2
]}

Cho, Nam-Chul ^{[2
,4
]}

Bhattarai, Deepak ^{[2
,3
]}

Kang, Soon Bang ^{[2
]}

Kim, Youseung ^{[2
]}

Pae, Ae Nim ^{[2
]}

Rhim, Hyewhon ^{[1
,3
]}

Keum, Gyochang ^{[2
,3
]}

机构：

[1] Korea Inst Sci & Technol, Ctr Neurosci, Brain Sci Inst, Seoul 136791, South Korea

[2] Korea Inst Sci & Technol, Ctr Neuromed, Brain Sci Inst, Seoul 136791, South Korea

[3] Univ Sci & Technol, Dept Biomol Sci, Taejon 305350, South Korea

[4] Yonsei Univ, Dept Biotechnol, Seoul 120749, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 07期

关键词：

mAChR receptor; M-1; agonist; 2-Pyrrolidone; Isoxazoline; Amyloid precursor protein; AMYLOID PRECURSOR PROTEIN; ALLOSTERIC MODULATION; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; ACTIVATION; BETA; PHARMACOLOGY; COGNITION; EMPHASIS; KINASE;

D O I：

10.1016/j.bmcl.2015.02.012

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of azacyclic compounds substituted with isoxazole and 5-substituted isoxazolines were synthesized as acyclic modifications of the oxime class M-1 mACh receptor agonist. Among them, 3-(tetrahydropyrin-3-yl)-5-(2-pyrrolodin-1-yl) isoxazoline compound 4f displayed potent and selective M1 mACh receptor agonist activity in the functional calcium mobilization assay (EC50 = 31 nM). Introduction of 2-pyrrolidinone and 3-tetrahydropyridine groups are pivotal to the high potency. Moreover, 4f was found to facilitate non-amyloidogenic amyloid precursor protein (APP) processing by significantly increasing ERK1/2 phosphorylation and sAPP alpha secretion, known disease-modifying effects related to M1 mAChR agonists in Alzheimer's disease (AD). (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：1546 / 1551

页数：6

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