A novel GABAA receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo.
A novel GABAA receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo.
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一种新型 GABAA 受体配体 MIDD0301 具有有限的血脑屏障渗透性，可在体内和体外放松气道平滑肌。
DOI：
10.1152/ajplung.00356.2018
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
EmalaSr,CharlesW
中科院分区：
文献类型：
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作者：
Yocum,GeneT;Perez-Zoghbi,JoseF;Danielsson,Jennifer;Kuforiji,AishaS;Zhang,Yi;Li,Guanguan;RashidRoni,MS;Kodali,Revathi;Stafford,DouglasC;Arnold,LeggyA;Cook,JamesM;EmalaSr,CharlesW
气道平滑肌（ASM）细胞表达GABAA受体（GABAAR），并且先前的报道已经证明GABAAR激活剂使ASM松弛。然而，考虑到GABAAR在中枢神经系统抑制性神经传递中的活性，存在这些活化剂可能导致不期望的镇静作用的担忧。MIDD 0301是一种新型咪唑并苯二氮卓类药物，是GABAAR的正变构调节剂，脑分布有限，因此消除了镇静作用的可能性。在这里，我们证明MIDD 0301放松组胺收缩豚鼠（P<0.05，n = 6-9）与人（P<0.05，n = 6-10）器官浴实验中离体气管平滑肌，精密切割肺切片实验中离体小鼠外周气道扩张（P<0.001，n = 3只小鼠的16个气道），并通过强迫振荡技术评估小鼠体内支气管收缩（P<0.05，n = 6只小鼠）。在吸入雾化的5 mM MIDD 0301后，在小鼠脑中仅检测到痕量浓度的化合物。鉴于其有利的药代动力学特性和在许多临床相关实验范例中证明的松弛ASM的能力，MIDD 0301是用于支气管收缩性疾病（例如哮喘）的有希望的候选药物。
Airway smooth muscle (ASM) cells express GABA A receptors (GABAARs), and previous reports have demonstrated that GABAAR activators relax ASM. However, given the activity of GABAARs in central nervous system inhibitory neurotransmission, concern exists that these activators may lead to undesirable sedation. MIDD0301 is a novel imidazobenzodiazepine and positive allosteric modulator of the GABAAR with limited brain distribution, thus eliminating the potential for sedation. Here, we demonstrate that MIDD0301 relaxes histamine-contracted guinea pig (P< 0.05,n= 6–9) and human (P< 0.05,n= 6–10) tracheal smooth muscle ex vivo in organ bath experiments, dilates mouse peripheral airways ex vivo in precision-cut lung-slice experiments (P< 0.001,n= 16 airways from three mice), and alleviates bronchoconstriction in vivo in mice, as assessed by the forced-oscillation technique (P< 0.05,n= 6 mice). Only trace concentrations of the compound were detected in the brains of mice after inhalation of nebulized 5 mM MIDD0301. Given its favorable pharmacokinetic properties and demonstrated ability to relax ASM in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases, such as asthma.