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. Epub 2015 Feb 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Molecular Structure
  • Receptor, Muscarinic M1 / agonists*
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Receptor, Muscarinic M1