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Nicotinic acid receptor subtypes and their ligands.
Med Res Rev. 2007 May; 27(3):417-33.MR

Abstract

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)low 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.

Authors+Show Affiliations

Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

17238156

Citation

Soudijn, Willem, et al. "Nicotinic Acid Receptor Subtypes and Their Ligands." Medicinal Research Reviews, vol. 27, no. 3, 2007, pp. 417-33.
Soudijn W, van Wijngaarden I, Ijzerman AP. Nicotinic acid receptor subtypes and their ligands. Med Res Rev. 2007;27(3):417-33.
Soudijn, W., van Wijngaarden, I., & Ijzerman, A. P. (2007). Nicotinic acid receptor subtypes and their ligands. Medicinal Research Reviews, 27(3), 417-33.
Soudijn W, van Wijngaarden I, Ijzerman AP. Nicotinic Acid Receptor Subtypes and Their Ligands. Med Res Rev. 2007;27(3):417-33. PubMed PMID: 17238156.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nicotinic acid receptor subtypes and their ligands. AU - Soudijn,Willem, AU - van Wijngaarden,Ineke, AU - Ijzerman,Adriaan P, PY - 2007/1/24/pubmed PY - 2007/6/6/medline PY - 2007/1/24/entrez SP - 417 EP - 33 JF - Medicinal research reviews JO - Med Res Rev VL - 27 IS - 3 N2 - 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)low 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. SN - 0198-6325 UR - https://www.unboundmedicine.com/medline/citation/17238156/Nicotinic_acid_receptor_subtypes_and_their_ligands_ L2 - https://doi.org/10.1002/med.20102 DB - PRIME DP - Unbound Medicine ER -