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Effects of pyrazole partial agonists on HCA 2 ‐mediated flushing and VLDL‐triglyceride levels in mice
Author(s) -
Li Zhaosha,
Blad Clara C,
van der Sluis Ronald J,
de Vries Henk,
Van Berkel Theo JC,
IJzerman Adriaan P,
Hoekstra Menno
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02039.x
Subject(s) - niacin , partial agonist , chemistry , triglyceride , endocrinology , medicine , pharmacology , potency , very low density lipoprotein , adipose tissue , in vivo , apolipoprotein b , antagonist , receptor , cholesterol , lipoprotein , in vitro , biochemistry , biology , microbiology and biotechnology
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 HCA 2 . In the current study, we evaluated two partial agonists for HCA 2 , LUF6281 and LUF6283, with respect to their anti‐dyslipidaemic potential and cutaneous flushing effect. EXPERIMENTAL APPROACH In vitro potency and efficacy studies with niacin and the two HCA 2 partial agonists were performed using HEK293T cells stably expressing human HCA 2 . Normolipidaemic C57BL/6 mice received either niacin or the HCA 2 partial agonists (400 mg·kg −1 ·day −1 ) once a day for 4 weeks for evaluation of their effects in vivo . KEY RESULTS Radioligand competitive binding assay showed K i values for LUF6281 and LUF6283 of 3 and 0.55 µM. [ 35 S]‐GTPγS binding revealed the rank order of their potency as niacin > LUF6283 > LUF6281. All three compounds reduced plasma VLDL‐triglyceride concentrations similarly, while LUF6281 and LUF6283, in contrast to niacin, did not also exhibit the unwanted flushing side effect in C57BL/6 mice. Niacin reduced the expression of lipolytic genes HSL and ATGL in adipose tissue by 50%, whereas LUF6281 and LUF6283 unexpectedly did not. In contrast, the decrease in VLDL‐triglyceride concentration induced by LUF6281 and LUF6283 was associated with a parallel >40% reduced expression of APOB within the liver. CONCLUSIONS AND IMPLICATIONS The current study identifies LUF6281 and LUF6283, two HCA 2 partial agonists of the pyrazole class, as promising drug candidates to achieve the beneficial lipid lowering effect of niacin without producing the unwanted flushing side effect.