Acifran is a well-known agonist of G-protein-coupled receptor protein, namely GPR109A. Acifran is primarily used in the treatment of dyslipidemia, myocardial infractions, and atherosclerosis in humans due to its lower vascular and metabolic side effects. However, experimental and computational studies on interaction sites of acifran with GPR proteins (GPR109A and GPR109B) are lacking. Our computational studies using docking and molecular dynamics simulation revealed that acifran binds distinctly to both GPR109A and GPR109B, but with lower affinity to the latter. The weak binding of acifran-GPR109B is mainly due to the presence of residues S91 and N94 in ECL1 and I178 amino acid in ECL2 region of GPR109B, whereas R111 and R251 residues in TMH3 and TMH6 are crucial for GPR109A-acifran complex stability. Additionally, molecular mechanics/Poisson-Boltzmann solvent accessible surface area (MM/PBSA) analysis revealed that both GPR109A- and GPR109B-acifran complexes are energetically stable with lower calculated binding free energy values for the latter. Energy-minimized structures of GPR109A-acifran and GPR109B-acifran complex.

01 Dec 2014·AtherosclerosisQ2 · MEDICINE

Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity

Q2 · MEDICINE

Article

Author: Hughes-Large, Jennifer M ; Robson, Debra L ; Pang, Dominic K T ; Toma, Jelena ; Chan, Pak ; Borradaile, Nica M

OBJECTIVENiacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD(+), niacin could elicit these vascular benefits through NAD(+)-dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved.METHODS AND RESULTSAngiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 μM), or nicotinamide mononucleotide (NMN) (1 μM), a direct NAD(+) precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD(+) and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin.CONCLUSIONNiacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD(+) biosynthesis and SIRT1 activation, but rather through niacin receptor activation.

01 Apr 2007·Journal of Medicinal ChemistryQ1 · MEDICINE

Analogues of Acifran: Agonists of the High and Low Affinity Niacin Receptors, GPR109a and GPR109b

Q1 · MEDICINE

Article

Author: Gharbaoui, Tawfik ; Connolly, Daniel T. ; Johnson, Benjamin R. ; Semple, Graeme ; Chen, Ruoping ; Duong, Tracy ; Richman, Jeremy G. ; Uy, Jane ; Jung, Jae-Kyu ; Boatman, P. Douglas ; Decaire, Marc ; Sage, Carleton R.

Recently identified GPCRs, GPR109a and GPR109b, the high and low affinity receptors for niacin, may represent good targets for the development of HDL elevating drugs for the treatment of atherosclerosis. Acifran, an agonist of both receptors, has been tested in human subjects, yet until recently very few analogs had been reported. We describe a series of acifran analogs prepared using newly developed synthetic pathways and evaluated as agonists for GPR109a and GPR109b, resulting in identification of compounds with improved activity at these receptors.

100 Deals associated with Acifran

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KEGG	Wiki	ATC	Drug Bank
D02753	Acifran	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 3	US	Wyeth Ltd. (India)	-
Hyperlipidemias	Phase 3	-	Pfizer Inc.	-

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