用于治疗鼻炎的长效双功能毒蕈碱M3和组胺H1受体拮抗剂的发现

文献信息

中文摘要

鼻炎是上气道黏膜的一种异质性炎症性疾病。慢性症状常对一线鼻内抗组胺药和糖皮质激素难治，尤其是在混合型和非过敏性表型中。附加抗胆碱能治疗可缓解流涕，但受限于作用时间短和每日多次给药。本文描述了一类独特的异源双功能M3/H1双重拮抗剂，设计用于每日一次鼻内治疗。通过调节一种新型双功能骨架——该骨架将基于二芳基砜的毒蕈碱拮抗剂与多种抗组胺化学型结合——开发出强效双作用配体，其全身暴露可忽略不计，且在鼻黏膜中滞留时间延长（>24 h）。先导化合物30/34（M3KB = 120/122 nM，H1KB = 4.60/6.72 nM）在豚鼠中抑制辣椒素诱导的非过敏性鼻炎症状，效果与对照药（异丙托溴铵/奥洛他定）相似；而在卵白蛋白诱导的小鼠过敏性鼻炎中，34达到与地塞米松/异丙托溴铵相当的 symptom control，并抑制警报素细胞因子（IL-33/TSLP）。这些发现支持进一步开发双靶点抗毒蕈碱/抗组胺药物，作为难治性鼻炎的长效治疗药物。

英文摘要

Rhinitis is a heterogeneous inflammatory condition of the upper airway mucosa. Chronic symptoms are often refractory to first-line intranasal antihistamines and corticosteroids, particularly in mixed and nonallergic phenotypes. Add-on anticholinergic treatment alleviates rhinorrhea but is hampered by short duration of action and multiple daily administrations. We describe here unique heterobifunctional M3/H1 dual antagonists designed for once-daily intranasal treatment. By tuning a novel bifunctional scaffold combining a diarylsulfone-based muscarinic antagonist with various antihistamine chemotypes, potent dual-acting ligands were developed with negligible systemic exposure and prolonged residence in nasal mucosa (>24 h). Lead compounds 30/34 (M3KB = 120/122 nM, H1KB = 4.60/6.72 nM, respectively) suppressed capsaicin-induced nonallergic rhinitis symptoms in guinea pigs similarly to comparators (ipratropium/olopatadine), while in ovalbumin-induced allergic rhinitis in mice, 34 achieved equivalent symptom control to dexamethasone/ipratropium and inhibited alarmin cytokines (IL-33/TSLP). These findings support further development of dual-targeting antimuscarinic/antihistamine agents as long-acting therapeutics for refractory rhinitis.