Università di Modena e Reggio Emilia, Dipartimento di Scienze Farmaceutiche, Via Campi 183, 41100 Modena, Italy.
Future Med Chem. 2009 Apr;1(1):157-77. doi: 10.4155/fmc.09.9.
Ghrelin is a peptide produced predominantly in the stomach and intestines, and is a natural growth hormone (GH) secretagogue-receptor ligand. It is able to stimulate GH release, but it also exhibits an important role in conditions related to processes regulating nutrition, body composition and growth, and heart, liver, thyroid or kidney dysfunction. Drug discovery efforts initially focused on ghrelin-receptor agonists, known as GH secretagogues, to be used as anabolic agents, but none of them reached the market.
The latest developments in this field are constituted by the discovery of new nonpeptidic compounds endowed with interesting properties: oxindole agonists are able to exert an increase in the fat-free mass, while ghrelin was reported to increase the fat mass gain, and triazole- and 2,4-diaminopyrimidine-based antagonists were shown to be able to reduce food intake, without inhibition of GH secretion stimulated by an agonist to the ghrelin receptor. Other antagonist compounds (quinazolinones) were discovered as antiobesity/antidiabetic agents. Moreover, inverse agonists have been discovered that are able to reduce weight gain.
Taking into account the great number of pathological conditions related to ghrelin, and the discovery of several compounds able to modulate the ghrelin receptor, its importance in the field of medicinal chemistry research is set to increase significantly.
Ghrelin 主要在胃和肠道中产生，是一种天然生长激素（GH）促分泌素受体配体。它能够刺激 GH 释放，但它在与调节营养、身体成分和生长以及心脏、肝脏、甲状腺或肾脏功能障碍相关的条件中也发挥着重要作用。药物发现工作最初集中在 ghrelin 受体激动剂上，称为 GH 促分泌素，用作合成代谢剂，但没有一种达到市场。
该领域的最新进展是发现了具有有趣特性的新型非肽化合物：吲哚酮激动剂能够增加无脂肪质量，而 ghrelin 被报道能够增加脂肪质量增加，并且报道了三唑和 2,4-二氨基嘧啶基为基础的拮抗剂能够减少食物摄入，而不抑制 ghrelin 受体激动剂刺激的 GH 分泌。其他拮抗剂化合物（喹唑啉酮）被发现为抗肥胖/抗糖尿病剂。此外，还发现了反向激动剂，能够减轻体重增加。
考虑到与 ghrelin 相关的大量病理状况，以及发现了几种能够调节 ghrelin 受体的化合物，它在药物化学研究领域的重要性将显著增加。
