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

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.