Design and synthesis of 2-(2,2-diarylethyl)-cyclamine derivatives as M3 receptor antagonists and functional evaluation on COPD.
Bioorg Chem
; 131: 106308, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36516520
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antagonistas Muscarínicos
/
Doença Pulmonar Obstrutiva Crônica
Limite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2023
Tipo de documento:
Article