Dopamine D3 receptor antagonists.: 1.: Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans
Dopamine D3 receptor antagonists.: 1.: Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans
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DOI：
10.1021/jm010145w
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发表时间：
2001-12-20
影响因子：
7.3
通讯作者：
Lin, CH
中科院分区：
文献类型：
--
作者：
Haadsma-Svensson, SR;Cleek, KA;Lin, CH
5，6-二甲氧基-2-（N-二丙基）-氨基茚满（3，PNU-99194 A）是一种选择性多巴胺D-3受体拮抗剂，在动物模型中具有潜在的抗精神病特性。为了研究氮取代对结构-活性关系的影响，合成了一系列5，6-二甲氧基-N-烷基-和N-烷基芳基-取代的2-氨基茚满，并在体外评价结合亲和力和代谢稳定性。结果表明，为了获得选择性D-3拮抗剂，在2-氨基茚满的胺氮上的取代相当限于二-N-丙基。因此，各种烷基的组合通常对D-3受体无活性。虽然用N-烷基芳基或N-烷基杂芳基取代产生具有有效D-3结合亲和力的化合物，但D-2亲和力也增强，导致对D-3受体位点的偏好小于4倍，并且未观察到代谢稳定性的改善。已经开发了D-3拮抗剂3的大规模合成，该合成已被证明是可重复的，只需很少的纯化步骤。这些改进包括使用3，4-二甲氧基苯甲醛作为低成本的起始原料，以良好的总产率（65%）提供所需的5，6-二甲氧基-1-茚满酮5c，以及形成可溶性甲硅烷基肟17，该甲硅烷基肟17被BH 3有效还原。Me2S将得到的氨基醇烷基化，然后用刘易斯酸和Et 3SiH脱氧，从茚满酮5c以良好的总产率（类似于65%）得到所需产物3。
5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D-3 receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D-3 antagonists. Thus, combinations of various alkyl groups were generally inactive at the D-3 receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D-3 binding affinity, the D-2 affinity is also enhanced, resulting in a less than 4-fold preference for the D-3 receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D-3 antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH3. Me2S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et3SiH to give the desired product 3 in good overall yield of (similar to 65%) from the indanone 5c.