title: Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74.
abstract: Niacin is known to exert profound beneficial effects on cholesterol levels in humans, although its use is somewhat hampered by the gram quantities necessary to exert effects and the prevalence of compliance-limiting skin flushing side effects that occur. Recently, two G protein-coupled receptors (GPCRs) for niacin were identified and characterized as high (HM74A; GPR109A) and low (HM74; GPR109B) affinity receptors based on the binding affinities of niacin. These receptors also bind acifran (AY-25,712), which is known to modulate lipid levels like niacin, with similar affinities. Twelve analogs of acifran were chemically synthesized. One analogue demonstrated a dose-dependent decrease in serum triglycerides in rats within 3h of oral administration. Next, the acifran analogs were assessed for their activity towards the high and low affinity niacin receptors expressed in CHO-K1 cells. Constructs expressing HM74A or HM74 were stably transfected into CHO-K1 cells and shown to elicit phosphorylation of p42 and p44 mitogen-activated protein kinase (ERK1/ERK2) phosphorylation upon addition of niacin or acifran. The presence of functionally coupled GPCRs was further confirmed using Pertussis toxin, which completely inhibited the ability of either niacin or acifran to elicit phospho-ERK1/ERK2. The EC(50) of p-ERK1/ERK2 for niacin for the high and low affinity receptors was 47nM and indeterminate (i.e., >100microM), respectively, while the EC(50) for acifran was 160 and 316nM, respectively. Two chemical analogs of acifran demonstrated robust phosphorylation of ERK1/ERK2. Collectively, these data suggest that the synthesis of acifran analogs may be a suitable path for developing improved HM74A agonists.
authors.affiliation: The Institute for Diabetes Discovery, 23 Business Park Drive, Branford, CT 06405, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Mahboubi
authors.forename: Terri
authors.initials: T
authors.lastname: Witman-Jones
authors.forename: Jean E
authors.initials: JE
authors.lastname: Adamus
authors.forename: Jack T
authors.initials: JT
authors.lastname: Letsinger
authors.forename: Darren
authors.initials: D
authors.lastname: Whitehouse
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Diane
authors.initials: D
authors.lastname: Sawicki
authors.forename: Nils
authors.initials: N
authors.lastname: Bergenhem
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Ross
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D009525:Niacin / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood*
chemical_list: D005663:Furans; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D000960:Hypolipidemic Agents; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014280:Triglycerides; D009525:Niacin; C036804:acifran; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3