Effects of pyrazole partial agonists on HCA2‐mediated flushing and VLDL‐triglyceride levels in mice

  title={Effects of pyrazole partial agonists on HCA2‐mediated flushing and VLDL‐triglyceride levels in mice},
  author={Zhaosha Li and Clara C. Blad and Ronald J. van der Sluis and Henk de Vries and Th J C van Berkel and Adriaan P. IJzerman and Menno Hoekstra},
  journal={British Journal of Pharmacology},
BACKGROUND AND PURPOSE Niacin can effectively treat dyslipidaemic disorders. However, its clinical use is limited due to the cutaneous flushing mediated by the nicotinic acid receptor HCA2. In the current study, we evaluated two partial agonists for HCA2, LUF6281 and LUF6283, with respect to their anti‐dyslipidaemic potential and cutaneous flushing effect. 

G Protein-coupled Receptor Biased Agonism.

The theory and most recent breakthroughs in understanding biased signaling are summarized, recent laboratory investigations concerning biased ligands across different organ systems are examined, and the promising clinical applications of biased agonism are discussed.

New Insights into Modes of GPCR Activation.



Niacin use and cutaneous flushing: mechanisms and strategies for prevention.

  • M. Davidson
  • Medicine
    The American journal of cardiology
  • 2008

Future of GPR109A agonists in the treatment of dyslipidaemia

This review presents what is known to date about G PR109A biology and function and the future of GPR109A as a pharmacological target and suggests it could play a crucial part in its role as a lipid‐modifying drug.

Effects of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans.

GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing.

The data clearly indicate that GPR109A mediates nicotinic acid-induced flushing and that this effect involves release of PGE(2) and PGD(2), most likely from immune cells of the skin.

Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans.

  • K. ChengTsuei-ju Wu M. Waters
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans, and a clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA.

Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents?

Nicotinic acid receptor subtypes and their ligands

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.

Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors*

A number of GPR109A pyrazole agonists are identified that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicite a flush response in vivo.

Pyrazole derivatives as partial agonists for the nicotinic acid receptor.

A series of substituted pyrazole-3-carboxylic acids were synthesized that proved to have substantial affinity for the recently identified and cloned G protein-coupled nicotinic acid receptor, pointing to a competitive mechanism of action.

Niaspan, the prolonged release preparation of nicotinic acid (niacin), the broad‐spectrum lipid drug

  • L. Carlson
  • Medicine, Biology
    International journal of clinical practice
  • 2004
Niacin, now available as the well‐tolerable drug formulation Niaspan™, is the unique broad‐spectrum lipid drug for the prevention and treatment of clinical atherosclerosis.