Isoxazoline, Isoxazole, and Oxadiazole Derivatives as M1 Muscarinic Acetylcholine Receptor Agonists
Isoxazoline, Isoxazole, and Oxadiazole Derivatives as M1 Muscarinic Acetylcholine Receptor Agonists
Selvaraj Muthusamy(Korea Institute of Science and Technology (KIST)); 이수민(동국대학교); Minghua Huang(Korea University of Science and Technology); 조남철(Korea Institute of Science and Technology (KIST)); 남길수(한국과학기술연구원); Ae Nim Pae(Korea Institute of Science and Technology (KIST)); Hyewhon Rhim(Korea University of Science and Technology (UST)); 금교창(한국과학기술연구원); 최경일(한국과학기술연구원)
37권 7호, 1020~1028쪽
초록
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 μM) was five- to six-fold more effective than endo-isomer (EC50 0.30 μM), and ca. two-fold active than the mother compound 1 (EC50 0.031 μM) in stimulating the M1 mAChR. Both isomers were moderately selective agonists for M1 mAChR over the rest four subtypes, and it could be explained by docking study on active conformation allosteric binding sites of M1–M5 mAChRs and calculating their binding energies.
Abstract
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 μM) was five- to six-fold more effective than endo-isomer (EC50 0.30 μM), and ca. two-fold active than the mother compound 1 (EC50 0.031 μM) in stimulating the M1 mAChR. Both isomers were moderately selective agonists for M1 mAChR over the rest four subtypes, and it could be explained by docking study on active conformation allosteric binding sites of M1–M5 mAChRs and calculating their binding energies.
- 발행기관:
- 대한화학회
- 분류:
- 화학