RESUMEN
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
Asunto(s)
Antagonistas Muscarínicos/síntesis química , Tropanos/síntesis química , Animales , Enfermedades Bronquiales/tratamiento farmacológico , Diseño de Fármacos , Ratones , Antagonistas Muscarínicos/farmacología , Receptores Muscarínicos/efectos de los fármacos , Relación Estructura-Actividad , Tropanos/farmacologíaRESUMEN
The chemokine CXCL10 is produced by many inflammatory cells found in the diseased lung and has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The present study demonstrates elevated CXCL10 protein in the lungs of COPD patients, which appears histologically in airway smooth muscle (hASM). In primary cultured hASM cells taken from normal donors, CXCL10 protein expression was induced by IFN-gamma and TNF-alpha, cytokines reported as elevated in COPD, and a synergistic response was obtained when they were combined. TNF-alpha stimulation of hASM enhanced accumulation of CXCL10 mRNA, indicating regulation at the transcriptional level, while IFN-gamma stimulation resulted in a smaller accumulation of CXCL10 mRNA. When these cytokines were applied simultaneously, an additive effect was obtained. TNF-alpha-induced CXCL10 expression in hASM was dependent on NFkappaB activation, and a salicylanilide NFkappaB inhibitor blocked the CXCL10 expression. In contrast, IFN-gamma stimulation resulted in transient NFkappaB activation, and the inhibitor had little effect on CXCL10 expression. When these cytokines were added simultaneously, NFkappaB was activated earlier and lasted longer, and the effect was blocked by the inhibitor. These data demonstrate a potential active role for hASM in pulmonary inflammatory diseases such as COPD by producing CXCL10.
Asunto(s)
Quimiocinas CXC/biosíntesis , Interferón gamma/farmacología , Pulmón/inmunología , Músculo Liso/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Células Cultivadas , Quimiocina CXCL10 , Sinergismo Farmacológico , Humanos , Inflamación/inmunología , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/patología , Receptores CXCR3 , Receptores de Quimiocina/metabolismo , Sistema Respiratorio/anatomía & histologíaRESUMEN
Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.