Target Information

Target General Infomation
Target ID
T00864
Former ID
TTDI00462
Target Name
Nicotinic acid receptor 1
Gene Name
HCAR2
Synonyms
Gprotein coupled receptor 109A; Gprotein coupled receptor HM74A; Hydroxycarboxylic acid receptor 2; Niacin receptor 1; Nicotinic acid receptor; HCAR2
Target Type
Clinical Trial
Disease Arteriosclerosis [ICD9: 440; ICD10: I70]
Atherosclerosis [ICD9: 414.0, 440; ICD10: I70]
Acute ischemic stroke [ICD9: 434.91; ICD10: I61-I63]
Cardiovascular disorder [ICD10: I00-I99]
Hyperlipidaemia [ICD9: 272.0-272.4; ICD10: E78]
Major depressive disorder [ICD9: 296.2, 296.3, 710.0; ICD10: F32, F33, M32]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Function
Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5- methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.
BioChemical Class
GPCR rhodopsin
UniProt ID
Q8TDS4
Sequence
MNRHHLQDHFLEIDKKNCCVFRDDFIVKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWK
SSRIFLFNLAVADFLLIICLPFLMDNYVRRWDWKFGDIPCRLMLFMLAMNRQGSIIFLTV
VAVDRYFRVVHPHHALNKISNRTAAIISCLLWGITIGLTVHLLKKKMPIQNGGANLCSSF
SICHTFQWHEAMFLLEFFLPLGIILFCSARIIWSLRQRQMDRHAKIKRAITFIMVVAIVF
VICFLPSVVVRIRIFWLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPS
FPNFFSTLINRCLQRKMTGEPDNNRSTSVELTGDPNKTRGAPEALMANSGEPWSPSYLGP
TSP
Drugs and Mode of Action
Drug(s) GSK-256073 Drug Info Phase 2 Hyperlipidaemia [532371], [543157]
MK-1903 Drug Info Phase 2 Arteriosclerosis [522585], [541104]
SCH-900271 Drug Info Phase 2 Acute ischemic stroke [532808], [543156]
INCB19602 Drug Info Discontinued in Phase 2 Type 2 diabetes [548702]
Agonist (+)-5-(5-bromothiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid Drug Info [527576]
3-pyridine-acetic acid Drug Info [535672]
5-methyl nicotinic acid Drug Info [535672]
beta-D-hydroxybutyric acid Drug Info [527576]
cinnamic acid Drug Info [529913]
compound (+)17a Drug Info [530828]
compound 1q Drug Info [529163]
compound 21 Drug Info [531315]
compound 2g Drug Info [530032]
compound 8f Drug Info [531020]
GPR109A agonists, Merck Drug Info [532808]
GSK-256073 Drug Info [532371], [532808]
MK-1903 Drug Info [532014], [532808]
MK-6892 Drug Info [532808]
monomethylfumarate Drug Info [529650]
[3H]nicotinic acid Drug Info [526577]
Modulator (allosteric modulator) compound 42 Drug Info [531844]
compound 9n Drug Info [529657]
Modulator INCB19602 Drug Info
SCH-900271 Drug Info [532808]
Binder Sazetidine-A Drug Info [532808]
Pathways
KEGG Pathway cAMP signaling pathway
Reactome Class A/1 (Rhodopsin-like receptors)
G alpha (i) signalling events
WikiPathways GPCR ligand binding
GPCR downstream signaling
References
Ref 522585ClinicalTrials.gov (NCT00847197) A Study to Evaluate MK1903 in Patients With Dyslipidemia (MK1903-004). U.S. National Institutes of Health.
Ref 532371GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Nov;15(11):1013-21.
Ref 532808Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia. ACS Med Chem Lett. 2011 Nov 24;3(1):63-8.
Ref 541104(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5785).
Ref 543156(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8469).
Ref 543157(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8470).
Ref 548702Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027843)
Ref 526577Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun. 2003 Mar 28;303(1):364-9.
Ref 527576(D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005 Jul 22;280(29):26649-52. Epub 2005 Jun 1.
Ref 529163Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A. Bioorg Med Chem Lett. 2007 Dec 15;17(24):6723-8. Epub 2007 Oct 18.
Ref 529650The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun. 2008 Oct 31;375(4):562-5.
Ref 529657Discovery of pyrazolopyrimidines as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4948-51.
Ref 529913Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J Lipid Res. 2009 May;50(5):908-14.
Ref 530032Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats. J Med Chem. 2009 Apr 23;52(8):2587-602.
Ref 530828Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a). Bioorg Med Chem Lett. 2010 May 1;20(9):2797-800.
Ref 531020Bioorg Med Chem Lett. 2010 Aug 1;20(15):4472-4. Epub 2010 Jun 10.GPR109a agonists. Part 2: pyrazole-acids as agonists of the human orphan G-protein coupled receptor GPR109a.
Ref 531315The discovery of high affinity agonists of GPR109a with reduced serum shift and improved ADME properties. Bioorg Med Chem Lett. 2011 May 1;21(9):2721-4.
Ref 531844Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2 (GPR109A). J Med Chem. 2012 Apr 12;55(7):3563-7.
Ref 532014Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 2012 Aug 22;4(148):148ra115.
Ref 532371GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Nov;15(11):1013-21.
Ref 532808Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia. ACS Med Chem Lett. 2011 Nov 24;3(1):63-8.
Ref 535672Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003 Mar 14;278(11):9869-74. Epub 2003 Jan 9.

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