期刊
BIOORGANIC CHEMISTRY
卷 131, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.106308
关键词
Muscarinic acetylcholine receptor; COPD; M3 antagonist; O -substituted cyclamine; Tracheo-relaxation
A series of 2-(2,2-diarylethyl)-cyclamine derivatives were designed and synthesized as M3 mAChR antagonists, showing excellent selectivity and antagonistic activity. These novel compounds have the potential to be candidates for COPD drug development.
Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diary-lethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear struc-ture-activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC50 value of 3 nM and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Such excellent properties made these novel compounds potential candidates for COPD drug development.
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