Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson's Disease
Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson's Disease
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DOI：
10.1021/acs.jmedchem.0c00914
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发表时间：
2021-06-09
影响因子：
7.3
通讯作者：
Stark, Holger
中科院分区：
文献类型：
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作者：
Hagenow, Stefanie;Affini, Anna;Stark, Holger
腺苷A（1）/A（2A）受体（A（1）R/A（2A）R）代表运动障碍如帕金森病（PD）的非多巴胺能治疗的靶点。作为一种创新策略，开发了多靶向配体（MTL），以实现全面的PD治疗，同时解决睡眠中断等共病症状。认识到组胺H-3受体（H3 R）拮抗剂的促醒能力与A（1）R/A（2A）R拮抗剂的“咖啡因样效应”的组合，我们设计了A（1）R/A（2A）R/H3 R MTLs，其中哌啶子基-/吡咯烷基（丙氧基）苯基H3 R药效团以重叠方式引入腺苷拮抗剂芳基茚并嘧啶核心。这些MTL显示出具有总体纳摩尔H3 R亲和力（Ki < SS nM）的不同受体结合谱。在体内评价化合物4（ST-2001，Ki（A（I）R）= 11.5nM，（A（2A）R）= 7.25nM）和12（ST-1992，Ki（A（I）R）= 11.2nM，Ki（A（2A）R）= 4.01nM）。（L）-DOPA诱导的运动障碍在施用化合物4（1 mg/kg，大鼠腹膜内）后得到改善。将化合物12（2 mg kg（-1），p.o.小鼠）增加的觉醒，代表了用于PD治疗的新的药理学工具。
Adenosine A(1)/A(2A), receptors (A(1)R/A(2A)R) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H-3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A(1)R/A(2A)R antagonists, we designedA(1)R/A(2A)R/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (K-i < SS nM). Compound 4 (ST-2001, K-i (A(1)R) = 11.5 nM, (A(2A)R) = 7.25 nM) and 12 (ST-1992, K-i (A(1)R) = 11.2 nM, K-i (A(2A)R) = 4.01 nM) were evaluated in vivo. (L)-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg(-1), i.p. rats). Compound 12 (2 mg kg(-1), p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.