2. Academic Validation
  3. Synthesis and biological evaluation of isoxazoline derivatives as potent M₁ muscarinic acetylcholine receptor agonists

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

  • Bioorg Med Chem Lett. 2015 Apr 1;25(7):1546-51. doi: 10.1016/j.bmcl.2015.02.012.
Minghua Huang 1,  Dae-Hwan Suk 2,  Nam-Chul Cho 3,  Deepak Bhattarai 4,  Soon Bang Kang 2,  Youseung Kim 2,  Ae Nim Pae 2,  Hyewhon Rhim 5,  Gyochang Keum 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 25765911 DOI: 10.1016/j.bmcl.2015.02.012
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).

Keywords

2-Pyrrolidone; Amyloid precursor protein; Isoxazoline; M(1) agonist; mAChR receptor.

Figures