Synthesis and SAR exploration of dinapsoline analogues.
Synthesis and SAR exploration of dinapsoline analogues.
复制标题
地那酚类似物的合成及SAR探索。
DOI：
10.1016/j.bmc.2003.11.015
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Mailman,
中科院分区：
文献类型：
--
作者：
Sit,Sing-Yuen;Xie,Kai;Jacutin-Porte,Swanee;Boy,KennethM;Seanz,James;Taber,MatthewT;Gulwadi,AmitG;Korpinen,CarolynD;Burris,KevinD;Molski,ThaddeusF;Ryan,Elaine;Xu,Cen;Verdoorn,Todd;Johnson,Graham;Nichols,DavidE;Mailman,
地那普索林是一种完全的D1多巴胺受体激动剂，在单侧6-OHDA大鼠模型中产生强大的旋转活性。该化合物是口服活性的，并且在大鼠模型中显示出引起耐受性的低趋势。活性对映异构体被确定为具有S-（+）构型，而相反的对映异构体基本上没有生物活性。综上所述，地那普索林具有显着的代谢和药理学优势，比以前的D1受体激动剂。为了定义结构-活性关系（SAR）并绘制出围绕地那普索林独特结构的关键元素，制备了母体四环稠环结构的核心类似物和取代类似物。在地那普索林及其对映体合成的基础上，合成了地那普索林的A、B′、C、D四个环上的核心类似物和取代类似物。结果发现，A、B′和C环上的大多数取代基都降低了对D1和D2受体的亲和力，而D环取代保留了大部分多巴胺受体结合活性。
Dinapsoline is a full D1dopamine receptor agonist that produces robust rotational activity in the unilateral 6-OHDA rat model. This compound is orally active, and shows a low tendency to cause tolerance in rat models. The active enantiomer was determined to have the S-(+) configuration, and the opposite enantiomer is essentially devoid of biological activity. Taken together, dinapsoline has significant metabolic and pharmacological advantages over previous D1agonists. In an attempt to define the structure–activity relationships (SARs) and to map out the key elements surrounding the unique structure of dinapsoline, core analogues and substitution analogues of the parent tetracyclic condensed ring structure were prepared. Based on a recently developed synthesis of dinapsoline and its enantiomers, both core and substitution analogues on all four rings (A, B′, C and D ring) of dinapsoline were synthesized. It was found that affinity for both D1and D2receptors was decreased by most substituents on the A, B′, and C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity.