Huang, Minghua Suk, Dae-Hwan Cho, Nam-Chul Bhattarai, Deepak Kang, Soon Bang Kim, Youseung Pae, Ae Nim Rhim, Hyewhon Keum, Gyochang 2024-01-20T07:30:18Z 2024-01-20T07:30:18Z 2021-09-04 2015-04-01 0960-894X https://pubs.kist.re.kr/handle/201004/125559 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. English Pergamon Press Ltd. AMYLOID PRECURSOR PROTEIN ALLOSTERIC MODULATION CEREBROSPINAL-FLUID ALZHEIMERS-DISEASE ACTIVATION BETA PHARMACOLOGY COGNITION EMPHASIS KINASE Synthesis and biological evaluation of isoxazoline derivatives as potent M-1 muscarinic acetylcholine receptor agonists Article 10.1016/j.bmcl.2015.02.012 1 Bioorganic & Medicinal Chemistry Letters, v.25, no.7, pp.1546 - 1551 Bioorganic & Medicinal Chemistry Letters 25 7 1546 1551 scie scopus 000351688700036 2-s2.0-84925460879 Chemistry, Medicinal Chemistry, Organic Pharmacology & Pharmacy Chemistry Article AMYLOID PRECURSOR PROTEIN ALLOSTERIC MODULATION CEREBROSPINAL-FLUID ALZHEIMERS-DISEASE ACTIVATION BETA PHARMACOLOGY COGNITION EMPHASIS KINASE mAChR receptor M-1 agonist 2-Pyrrolidone Isoxazoline Amyloid precursor protein