Isoxazoline, Isoxazole, and Oxadiazole Derivatives as M-1 Muscarinic Acetylcholine Receptor Agonists

摘要

Insertion of a methylene linker between the 2-pyrrolidinone substituent and the isoxazoline core of the lead compound 1 previously reported resulted in the loss of its agonistic activity. One exception was the compound 6f having oxadiazole core and 2-azabicyclo[2.2.1]heptane substituent. Of the two isomers of 6f, exo-isomer (EC50 0.013 mu M) was five- to six-fold more effective than endo-isomer (EC50 0.30 mu M), and ca. two-fold active than the mother compound 1 (EC50 0.031 mu M) in stimulating the M-1 mAChR. Both isomers were moderately selective agonists for M-1 mAChR over the rest four subtypes, and it could be explained by docking study on active conformation allosteric binding sites of M-1-M-5 mAChRs and calculating their binding energies.