Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30 - 688 Krakow, Poland.
Curr Med Chem. 2018;25(14):1609-1626. doi: 10.2174/0929867325666171123203550.
Since its discovery in 1983, followed by gene cloning in 1999, the histamine H3 receptor served as an outstanding target for drug discovery. The wide spectrum of possible therapeutic implications makes H3R's one of the most researched areas in the vast GPCR ligands field - started from imidazole containing ligands, through various successful imidazole replacements, with recent introduction of Wakix® to pharmaceutical market. One such replacement is piperazine moiety, a significant versatile scaffold in rational drug design for most of the GPCR ligands. Therefore, herein, we review ligands built on piperazine, as well as its seven membered analogue azepine, that target H3R's and their potential therapeutical applications, in order to elucidate the current state of the art in this vast field. Due to a high level of structural divergence among compounds described herein, we decided to divide them into groups, where the key division element was the position of nitrogen basicity decreasing moieties in (homo)piperazine ring. Paying attention to a number of published structures and their overall high biological activity, one can realize that the (homo)piperazine scaffold bids a versatile template also for histamine H3 receptor ligands. With two possible substitution sites and therefore a number of possible structural combinations, piperazine derivatives stand as one of the largest group of high importance among H3R ligands.
自 1983 年发现组胺 H3 受体以来，1999 年又对其基因进行了克隆，该受体已成为药物发现的一个重要靶点。由于组胺 H3 受体具有广泛的治疗应用前景，因此它是广阔的 G 蛋白偶联受体配体领域中研究最多的领域之一——从含咪唑的配体开始，经过各种成功的咪唑替代物，最近 Wakix®已被引入药物市场。其中一种替代物是哌嗪部分，它是大多数 GPCR 配体合理药物设计中非常通用的支架。因此，本文综述了以哌嗪及其七元类似物氮杂环庚烷为基础构建的配体，以及它们作为组胺 H3 受体配体的潜在治疗应用，以阐明该领域的最新技术水平。由于本文所述化合物的结构差异很大，我们决定将它们分为几组，其中关键的分组元素是（同）哌嗪环中降低氮碱性部分的位置。考虑到许多已发表结构及其整体高生物活性，可以认识到（同）哌嗪支架也是组胺 H3 受体配体的一种通用模板。哌嗪衍生物有两个可能的取代位点，因此有许多可能的结构组合，是组胺 H3 受体配体中最重要的一类。
