Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States.
Department of Anesthesiology, Columbia University, New York, New York 10032, United States.
J Med Chem. 2023 Jul 27;66(14):9853-9865. doi: 10.1021/acs.jmedchem.3c00647. Epub 2023 Jul 7.
Novel gamma-aminobutyric acid receptor (GABAR) ligands structurally related to imidazobenzodiazepine MIDD0301 were synthesized using spiro-amino acid N-carboxyanhydrides (NCAs). These compounds demonstrated increased resistance to phase 2 metabolism and avoided the formation of a 6H isomer. Compound design was guided by molecular docking using the available crystal structure of the αβγ GABAR and correlated with in vitro binding data. The carboxylic acid containing GABAR ligands have high aqueous solubility, low permeability, and low cell toxicity. The inability of GABAR ligands to cross the blood-brain barrier was confirmed in vivo by the absence of sensorimotor inhibition. Pharmacological activities at lung GABARs were demonstrated by ex vivo relaxation of guinea pig airway smooth muscle and reduction of methacholine-induced airway hyperresponsiveness (AHR) in conscious mice. We identified bronchodilator with an affinity of 9 nM for GABARs that was metabolically stable in the presence of human and mouse microsomes.
新型γ-氨基丁酸受体（GABAR）配体与咪唑并苯并二氮杂䓬 MIDD0301 在结构上有关，使用螺环氨基酸 N-羧酸酐（NCAs）合成。这些化合物表现出对第二相代谢的抗性增加，避免了 6H 异构体的形成。通过使用可用的 αβγ GABAR 晶体结构进行分子对接指导化合物设计，并与体外结合数据相关联。含有羧酸的 GABAR 配体具有高水溶性、低渗透性和低细胞毒性。体内研究证实 GABAR 配体不能穿过血脑屏障，因为没有感觉运动抑制作用。通过豚鼠气道平滑肌的离体松弛和降低清醒小鼠中乙酰甲胆碱诱导的气道高反应性（AHR）来证明肺 GABAR 的药理学活性。我们鉴定出一种支气管扩张剂，对 GABAR 的亲和力为 9 nM，在人源和鼠源微粒体中具有代谢稳定性。
