Zhang Y, Williams W, Torrence-Campbell C, Bowen W D, Rice K C
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Drive, MSC 0815, Bethesda, Maryland 20892-0815, USA.
J Med Chem. 1998 Dec 3;41(25):4950-7. doi: 10.1021/jm980143k.
sigma Receptors have been the focus of extensive studies because of their potential functional role in several important physiological and biochemical processes. To further evaluate the properties of sigma receptors, especially sigma-1 and sigma-2 subtypes, we have synthesized a series of N,N'-disubstituted piperazine compounds (1-32). The design of these compounds was based upon the early structure-activity relationship (SAR) studies of the minimum structural requirements of a molecule necessary to elicit sigma receptor binding activity. In the N-(3-phenylpropyl)piperazine series, compounds with the ethylenediamine moiety (8-11, 15-17) showed 6-20-fold higher affinity for sigma-1 and 2-40-fold higher affinity for sigma-2 relative to their corresponding amides (1-7). The (m-nitrophenethyl)piperazine 10 exhibits a subnanomolar affinity for the sigma-1 site, whereas the corresponding o-nitro compound 9 shows the highest affinity for the sigma-2 site (Ki = 4.9 nM). Compounds with a free amino terminus were designed as precursors for use as bioconjugated affinity compounds. Some of these compounds displayed high affinity for sigma-1 and moderate affinity for sigma-2 sites and are currently used for the purification and characterization of the receptor subtypes.
西格玛受体因其在多个重要生理和生化过程中的潜在功能作用而成为广泛研究的焦点。为了进一步评估西格玛受体的特性，特别是西格玛-1和西格玛-2亚型，我们合成了一系列N,N'-二取代哌嗪化合物（1-32）。这些化合物的设计基于早期对引发西格玛受体结合活性所需分子最小结构要求的构效关系（SAR）研究。在N-(3-苯丙基)哌嗪系列中，含有乙二胺部分的化合物（8-11、15-17）对西格玛-1的亲和力比其相应的酰胺（1-7）高6-20倍，对西格玛-2的亲和力高2-40倍。(间硝基苯乙基)哌嗪10对西格玛-1位点表现出亚纳摩尔亲和力，而相应的邻硝基化合物9对西格玛-2位点表现出最高亲和力（Ki = 4.9 nM）。具有游离氨基末端的化合物被设计为用作生物共轭亲和化合物的前体。其中一些化合物对西格玛-1表现出高亲和力，对西格玛-2位点表现出中等亲和力，目前用于受体亚型的纯化和表征。
