Bivalent dopamine agonists with co-operative binding and functional activities at dopamine D2 receptors, modulate aggregation and toxicity of alpha synuclein protein.
Bivalent dopamine agonists with co-operative binding and functional activities at dopamine D2 receptors, modulate aggregation and toxicity of alpha synuclein protein.
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二价多巴胺激动剂与多巴胺 D2 受体具有协同结合和功能活性，调节 α 突触核蛋白的聚集和毒性。
DOI：
10.1016/j.bmc.2022.117131
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发表时间：
2023
影响因子：
3.5
通讯作者：
Dutta,AlokeK
中科院分区：
文献类型：
--
作者：
Dinda,Bidyut;Das,Banibrata;Biswas,Swati;Sharma,Horrick;Armstrong,Christopher;Yedlapudi,Deepthi;Antonio,Tamara;Reith,Maarten;Dutta,AlokeK
为了继续我们先前关于在多巴胺D2受体上显示出有效的协同结合的二价化合物的报道，我们修改了我们先前的二价分子（S）-6-（（9-（R）-5-羟基-1，2，3，4-四氢萘-2-基）（丙基）氨基）壬基）-（丙基）氨基）-5，6，7中的接头的结构，8-四氢萘-1-醇（Ia）和（S）-6-（（10-（R）-5-羟基-1，2，3，4-四氢萘-2-基）（丙基）氨基）癸基）（丙基）氨基）-5，6，7，8-四氢萘-1-醇（Ib）（图1）连接两个药效部分，以观察在维持相似亲和力和效力方面的任何耐受性。具体而言，我们在接头中引入芳香族和哌嗪部分以探索它们的效果。总体而言，在新分子中保持了与我们早期研究中观察到的D2受体相似的活性，例如（6S，6′S）-6，6 ′-（（1，4-亚苯基双（乙烷-2，1-二基））双（丙基氮烷二基））双（5，6，7，8-四氢萘-1-醇）（D-382）（Ki，D2 = 3.88 nM）。D-382中的芳香族部分接下来通过引入羟基来官能化，以模拟已知与淀粉样蛋白相互作用的多羟基天然产物。这样的转化导致化合物如2，5-双（2-（（（S）-5-羟基-1，2，3，4-四氢萘-2-基）（丙基）氨基）乙基）苯-1，4-二醇（D-666）（Ki，D2 = 7.62 nM）的开发，其对D2受体保持相似的亲和力和效力。这种二羟基化合物被证明是有效的抑制剂，对重组α突触核蛋白的聚集和毒性。本文报道的工作符合我们开发多功能多巴胺激动剂用于帕金森病的对症和疾病修饰治疗的总体目标。
To follow up on our previous report on bivalent compounds exhibiting potent co-operative binding at dopamine D2 receptors, we modified the structure of the linker in our earlier bivalent molecules (S)-6-((9-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)nonyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ia) and (S)-6-((10-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)decyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ib) (Fig. 1) connecting the two pharmaophoric moieties to observe any tolerance in maintaining similar affinities and potencies. Specifically, we introduced aromatic and piperazine moieties in the linker to explore their effect. Overall, similar activities at D2 receptors as observed in our earlier study was maintained in the new molecules e.g. (6S,6′S)-6,6′-((1,4-phenylenebis(ethane-2,1-diyl))bis(propylazanediyl))bis(5,6,7,8-tetrahydronaphthalen-1-ol) (D-382) (Ki, D2 = 3.88 nM). The aromatic moiety inD-382was next functionalized by introducing hydroxyl groups to mimic polyhydroxy natural products which are known to interact with amyloidogenic proteins. Such a transformation resulted in development of compounds like 2,5-bis(2-(((S)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)benzene-1,4-diol (D-666)(Ki, D2 = 7.62 nM) which retained similar affinity and potency at D2 receptors. Such dihydroxyl compounds turned out to be potent inhibitors against aggregation and toxicity of recombinant alpha synuclein protein. The work reported here is in line with our overall goal to develop multifunctional dopamine agonist for symptomatic and disease modifying treatment of Parkinson’s disease.