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Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74.
Biochem Biophys Res Commun. 2006 Feb 10; 340(2):482-90.BB

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+Show Affiliations

The Institute for Diabetes Discovery, 23 Business Park Drive, Branford, CT 06405, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16389067

Citation

Mahboubi, Keyvan, et al. "Triglyceride Modulation By Acifran Analogs: Activity Towards the Niacin High and Low Affinity G Protein-coupled Receptors HM74A and HM74." Biochemical and Biophysical Research Communications, vol. 340, no. 2, 2006, pp. 482-90.
Mahboubi K, Witman-Jones T, Adamus JE, et al. Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. Biochem Biophys Res Commun. 2006;340(2):482-90.
Mahboubi, K., Witman-Jones, T., Adamus, J. E., Letsinger, J. T., Whitehouse, D., Moorman, A. R., Sawicki, D., Bergenhem, N., & Ross, S. A. (2006). Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. Biochemical and Biophysical Research Communications, 340(2), 482-90.
Mahboubi K, et al. Triglyceride Modulation By Acifran Analogs: Activity Towards the Niacin High and Low Affinity G Protein-coupled Receptors HM74A and HM74. Biochem Biophys Res Commun. 2006 Feb 10;340(2):482-90. PubMed PMID: 16389067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. AU - Mahboubi,Keyvan, AU - Witman-Jones,Terri, AU - Adamus,Jean E, AU - Letsinger,Jack T, AU - Whitehouse,Darren, AU - Moorman,Allan R, AU - Sawicki,Diane, AU - Bergenhem,Nils, AU - Ross,Stuart A, Y1 - 2005/12/19/ PY - 2005/11/28/received PY - 2005/12/04/accepted PY - 2006/1/4/pubmed PY - 2006/3/18/medline PY - 2006/1/4/entrez SP - 482 EP - 90 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 340 IS - 2 N2 - 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. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/16389067/Triglyceride_modulation_by_acifran_analogs:_activity_towards_the_niacin_high_and_low_affinity_G_protein_coupled_receptors_HM74A_and_HM74_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(05)02768-3 DB - PRIME DP - Unbound Medicine ER -