Design and synthesis of 2-(2,2-diarylethyl)-cyclamine derivatives as M3 receptor antagonists and functional evaluation on COPD

[Display omitted] •Inspired by two active natural products, a series of 2-(2,2-diarylethyl)-cyclamine derivatives were designed and synthesized for screening M3 mAChR antagonists.•Compound 5b-C1 exhibited the highest M3 antagonistic activity with 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 good safety and comparable activity to tiotropium bromide, a known blockbuster drug for COPD. 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-diarylethyl)-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 structure–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.