title: Synthesis and biological evaluation of isoxazoline derivatives as potent M₁ muscarinic acetylcholine receptor agonists.
abstract: A series of azacyclic compounds substituted with isoxazole and 5-substituted isoxazolines were synthesized as acyclic modifications of the oxime class M1 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 sAPPα secretion, known disease-modifying effects related to M1 mAChR agonists in Alzheimer's disease (AD).
authors.affiliation: Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Minghua
authors.initials: M
authors.lastname: Huang
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Dae-Hwan
authors.initials: DH
authors.lastname: Suk
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biotechnology, Yonsei University 220, Seoul 120-749, Republic of Korea.
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Cho
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhattarai
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Soon Bang
authors.initials: SB
authors.lastname: Kang
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Youseung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.affiliation: Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: hrhim@kist.re.kr.
authors.forename: Hyewhon
authors.initials: H
authors.lastname: Rhim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: gkeum@kist.re.kr.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D007555:Isoxazoles; D043643:Receptor, Muscarinic M1
keywords: 2-Pyrrolidone; Amyloid precursor protein; Isoxazoline; M(1) agonist; mAChR receptor