期刊
MEDICINAL RESEARCH REVIEWS
卷 27, 期 3, 页码 417-433出版社
WILEY
DOI: 10.1002/med.20102
关键词
nicotinic acid; beta-hydroxybutyrate; nicotinic acid receptor; HM74A (GPR109A); HM74 (GPR109B); partial agonist; endogenous ligand; mutagenesis
Half a century ago, nicotinic acid (niacin) was introduced into the clinic as the first orally available drug to treat high cholesterol levels and to improve the balance between (V)Iow density lipoproteins (LDL) and high density lipoproteins (HDL). Remarkably, its putative mechanism of action has only been recently elucidated, particularly because of the cloning of a G protein-coupled receptor (HM74A or GPR109A). This receptor responds to both nicotinic acid and the ketone body beta-hydroxybutyrate, the latter thought to be the more probable endogenous ligand for HM74A. In this review, we will discuss the pharmacology and medicinal chemistry of this receptor subtype and a related one (HM74 or GPR109B). Although still in its infancy, the ligand repertoire is developing, and a number of compound classes have now been described, among which are both full and partial agonists. Antagonists, however, are still lacking, thus compromising thorough pharmacological studies. Mutagenesis experiments have provided clues regarding the ligand binding site; in particular, an arginine residue in transmembrane domain 3 of the receptor seems to recognize the acidic moiety present in nicotinic acid and related substances. HM74A has also been linked to one of the major side effects of nicotinic acid, that is, flushing, since this receptor subtype also occurs in skin immune cells. It is not known yet whether HM74 is also present on these cells. Since nicotinic acid is one of the few available medicines that raise HDL (good cholesterol) levels, HM74A and HM74 appear promising targets for future pharmacotherapy. (c) 2007 Wiley Periodicals, Inc.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据