Design of novel hexahydropyrazinoquinolines as potent and selective dopamine D3 receptor ligands with improved solubility
Design of novel hexahydropyrazinoquinolines as potent and selective dopamine D3 receptor ligands with improved solubility
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DOI：
10.1016/j.bmcl.2005.09.053
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发表时间：
2006-01-15
影响因子：
2.7
通讯作者：
Wang, SM
中科院分区：
文献类型：
--
作者：
Chen, JY;Ding, K;Wang, SM
我们最近报道了六氢吡嗪并喹啉作为一类新的多巴胺3（D-3）受体配体，其对D-3受体具有高亲和力，并且对密切相关的D-1样和D-2样受体具有优异的选择性。然而，我们以前报道的最有效的和选择性的D-3配体具有较差的水溶性，这极大地阻碍了我们旨在评估其在动物模型中的治疗潜力的体内研究。在本研究中，我们希望报道一系列新的六氢吡嗪并喹啉类化合物作为D-3配体的设计、合成和评价。其中，化合物4g对D-3受体的Ki值为9.7 nM，并且分别显示出超过D-1样受体和D-2样受体的>5000倍和466倍的选择性。重要的是，化合物4g的盐酸盐形式具有良好的水溶性（>50 mg/mL），并且代表了用于进一步体内评价其治疗药物滥用、不宁腿综合征、精神分裂症、帕金森病和抑郁症的治疗潜力的有前景的D-3配体。(c)2005爱思唯尔有限公司保留所有权利。
We have recently reported hexahydropyrazinoquinolines as a new class of dopamine 3 (D-3) receptor ligands with high-affinity to the D-3 receptor and excellent selectivity over the closely related D-1-like and D-2-like receptors. However, our previously reported most potent and selective D-3 ligands have poor aqueous solubility, which greatly hinders our in vivo studies aimed at evaluation of their therapeutic potential in animal models. In this study, we wish to report the design, synthesis, and evaluation of a series of new hexahydropyrazinoquinolines as D-3 ligands with improved solubility. Among them, compound 4g has a K-i value of 9.7 nM for the D-3 receptor and displays a selectivity of >5000 and 466 times over the D-1-like and D-2-like receptors, respectively. Importantly, the hydrochloride salt form of compound 4g has a good aqueous solubility (>50 mg/mL) and represents a promising D-3 ligand for further in vivo evaluations of its therapeutic potential for the treatment of drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease, and depression. (c) 2005 Elsevier Ltd. All rights reserved.