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  • In addition to their functional activation


    In addition to their functional activation of GPR109A, compounds of the pyrazolopyrimidine class also enhanced the binding of nicotinic Varlitinib australia to the receptor. For instance, increased the binding of H-nicotinic acid to the receptor (black curve) in a concentration-dependent manner, whereas unlabeled nicotinic acid displaced H-nicotinic acid from the receptor (red curve) (). We interpret enhanced H-nicotinic acid binding as indicative of positive allosteric modulation of the receptor, which taken together with the agonist properties of designates this compound as an allosteric agonist of GPR109A. The mechanism by which enhances H-nicotinic acid binding will be described elsewhere. Nicotinic acid has been shown to inhibit forskolin-stimulated cAMP accumulation in CHO-hGPR109A cells. A prediction of enhanced nicotinic acid binding to GPR109A in the presence of would be that the dose–response curve for nicotinic acid in this assay might be left-shifted. Like nicotinic acid, alone also induced the reduction of cAMP levels but with less magnitude (the bottom curve in ). Furthermore, potentiated the nicotinic acid-induced cAMP reduction in a dose-dependent fashion. As shown in , the effect of nicotinic acid on the cAMP accumulation was significantly left-shifted with increasing concentration of displaying a sensitization of nicotinic acid activity.
    Introduction Niacin (nicotinic acid, ) at high doses (>1 g/day) favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglyceride (TG), and lipoprotein a (Lp(a)) [1], [2]. Specifically, the ability of niacin to increase HDL-C (∼20%) is greater than any other drug on the market. As such niacin is considered a broad-spectrum lipid-lowering drug. On the other hand, along with the structurally closely related nicotinamide, niacin as vitamin B3 provides precursors to the coenzyme nicotinamide adenine dinucleotide, a vital electron receptor involved in the oxidation of fuel metabolites [3]. In a landmark study reported in 1955, niacin became the first drug to favorably affect plasma lipids [4]. Clinical data from the Coronary Drug Project (CDP) released in 1975 unequivocally demonstrated the effectiveness of niacin as the first drug to reduce atherosclerotic cardiovascular events [5], [6], [7], [8]. Over a 6-year dosing period, the niacin treatment cohort, which was administered a 2-g daily dose, experienced 26% fewer nonfatal myocardial infarctions and 24% fewer cerebrovascular events compared to the placebo group. In a follow-up study conducted 9 years after the completion of this trial, total mortality was reduced by 11% in patients originally treated with niacin in comparison to placebo-treated patients [9]. In the subsequent HATS [10] and ARBITER2 trials [11], the combination of niacin and simvastatin slowed the progression of atherosclerosis, reduced the number of cardiac events, and established further advantages over statin treatment alone. In addition, the Stockholm Ischaemic Heart Disease Study also achieved mortality reduction with the combination therapy of niacin and clofibrate [12]. The major adverse effect of niacin treatment is intense cutaneous flushing (vasodilation), which manifests as an uncomfortable burning sensation and itchiness of the face and upper body, thereby limiting patient compliance to therapy [13]. Moreover, a short half-life, dyspepsia, hyperuricemia, and modest hyperglycemia were also reported [14], [15], [16]. To attenuate vasodilation induced by niacin, four strategies have emerged. The first involves a once-daily extended-release formulation of niacin which substantially ameliorates the magnitude of flushing [17]. Based on the discovery that niacin causes prostaglandin D2 (PGD2) release in skin [18], and that antagonism of the PGD2 receptor DP1 suppresses niacin-induced vasodilation [19], the second strategy entails the combination of laropiprant (), a DP1 receptor antagonist and an extended release form of niacin. This combination has been shown to provide lipid effects similar to those of niacin alone, but with significantly diminished flushing symptoms [20]. As such, this combination was approved as Tredaptive in Europe in April 2008. The third approach is to take advantage of niacin derivatives with potential for reduced flushing. For example, in an in vitro assay to assess flushing, compound caused less PGD2 release by THP-1 macrophages than did niacin (34% vs. 100% respectively). On the other hand, compound was comparable to niacin for inhibiting HDL uptake by Hep-G2 cells (13% vs. 19% respectively), suggesting that and niacin may have similar HDL-raising activity [21]. In the same assays, compound provided similar PGD2 release (91%) with respect to niacin but more HDL uptake inhibition (30%). The fourth strategy involves development of agonists of the high-affinity niacin receptor and is the subject of this chapter.