Target Information

Target General Infomation
Target ID
T60182
Former ID
TTDS00439
Target Name
Glucagon receptor
Gene Name
GCGR
Synonyms
GLR; GCGR
Target Type
Successful
Disease Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1]
Hypoglycemia [ICD9: 250.8, 251.0, 251.1, 251.2, 270.3, 775.6, 962.3; ICD10: E16.0-E16.2]
Non-insulin dependent diabetes [ICD10: E11.9]
Obesity; Diabetes [ICD9: 250, 278; ICD10: E08-E13, E66]
Type 1 diabetes [ICD9: 250; ICD10: E10]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Function
G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system.
BioChemical Class
GPCR secretin
Target Validation
T60182
UniProt ID
P47871
Sequence
MPPCQPQRPLLLLLLLLACQPQVPSAQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNR
TFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQ
CQMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANL
FASFVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYC
WLLVEGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDN
MGFWWILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGV
HEVVFAFVTDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRL
GKVLWEERNTSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF
Drugs and Mode of Action
Drug(s) Glucagon recombinant Drug Info Approved Hypoglycemia [536361]
ISIS-GCGRrx Drug Info Phase 2 Diabetes [524338]
LY-2409021 Drug Info Phase 2 Type 2 diabetes [524685]
LY2944876 Drug Info Phase 2 Diabetes [524727]
PF-06291874 Drug Info Phase 2 Type 2 diabetes [524811]
LGD-6972 Drug Info Phase 1 Type 2 diabetes [524930]
SAR425899 Drug Info Phase 1 Diabetes [525144]
ZP2929 Drug Info Preclinical Obesity; Diabetes [551786]
BAY-27-9955 Drug Info Discontinued in Phase 1 Type 2 diabetes [540430], [547099]
BAY-73-7977 Drug Info Discontinued in Phase 1 Diabetes [548274]
NN-2501 Drug Info Discontinued in Phase 1 Type 2 diabetes [547689]
DIO-901 Drug Info Terminated Type 1 diabetes [548146]
NNC-252504 Drug Info Terminated Type 2 diabetes [547264]
Antagonist BAY-27-9955 Drug Info [526203]
BAY-73-7977 Drug Info [550160]
DSR-17759 Drug Info [543641]
hGCGR antagonist Drug Info [527303]
L-168049 Drug Info [543641]
LGD-6972 Drug Info [544477]
LY-2409021 Drug Info [533135]
MB-11262 Drug Info [543641]
NN-2501 Drug Info [547690]
NNC 92-1687 Drug Info [534773]
NNC-252504 Drug Info [528683]
PF-06291874 Drug Info [551494]
Inhibitor BI-32169 Drug Info [527224]
Des-His1[Glu9]glucagon-NH2 Drug Info [527432]
[des-His1,Tyr5,Glu9,D-Ala10]glucagon-NH2 Drug Info [534147]
[des-His1,Tyr5,Glu9,D-Phe10]glucagon-NH2 Drug Info [534147]
[des-His1,Tyr5,Glu9,D-Tyr10]glucagon-NH2 Drug Info [534147]
[des-His1,Tyr5,Glu9]glucagon-NH2 Drug Info [534147]
Agonist DIO-901 Drug Info [525683]
glucagon-(1-6) Drug Info [531513]
Binder DwLIP-GCGRrx Drug Info [551054]
Glucagon recombinant Drug Info [536409], [537009]
Modulator ISIS-GCGRrx Drug Info [1572591]
LY2944876 Drug Info [1572591]
MAR-531 Drug Info [543641]
SAR425899 Drug Info
ZP2929 Drug Info
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Glucagon signaling pathway
Reactome Glucagon signaling in metabolic regulation
G alpha (q) signalling events
G alpha (s) signalling events
Glucagon-type ligand receptors
WikiPathways GPCRs, Class B Secretin-like
Gastrin-CREB signalling pathway via PKC and MAPK
Integration of energy metabolism
GPCR ligand binding
GPCR downstream signaling
References
Ref 524338ClinicalTrials.gov (NCT01885260) Safety, Tolerability and Efficacy of ISIS-GCGRRx in Type 2 Diabetes. U.S. National Institutes of Health.
Ref 524685ClinicalTrials.gov (NCT02091362) A Study of LY2409021 on Blood Pressure and Pulse Rate in Participants With Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
Ref 524727ClinicalTrials.gov (NCT02119819) A Study to Compare a New Drug for Type 2 Diabetes to Placebo and to a Treatment Already Available for Type 2 Diabetes. U.S. National Institutes of Health.
Ref 524811ClinicalTrials.gov (NCT02175121) Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Study Of PF-06291874 As Oral Monotherapy To Treat Adults With Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
Ref 524930ClinicalTrials.gov (NCT02250222) Safety and Tolerability Study of Oral LGD-6972 for Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
Ref 525144ClinicalTrials.gov (NCT02411825) Multiple Ascending Dose Study in Healthy Male Subjects. U.S. National Institutes of Health.
Ref 536361Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
Ref 540430(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: 3491).
Ref 547099Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013061)
Ref 547264Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014586)
Ref 547689Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018428)
Ref 548146Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022421)
Ref 548274Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024072)
Ref 5517862011 Pipeline of Zealand Pharma.
Ref
Ref 525683Effects of low-dose and high-dose glucagon on glucose production and gluconeogenesis in humans. Metabolism. 2000 Jan;49(1):39-46.
Ref 526203Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia. 2001 Nov;44(11):2018-24.
Ref 527224J Nat Prod. 2004 Sep;67(9):1528-31.BI-32169, a bicyclic 19-peptide with strong glucagon receptor antagonist activity from Streptomyces sp.
Ref 527303A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes. 2004 Dec;53(12):3267-73.
Ref 527432Bioorg Med Chem Lett. 2005 Mar 1;15(5):1401-5.Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor.
Ref 528683A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. J Pharmacol Exp Ther. 2007 May;321(2):743-52. Epub 2007 Feb 16.
Ref 531513Glucagon1-6 binds to the glucagon receptor and activates hepatic adenylate cyclase. J Biol Chem. 1979 Jan 25;254(2):268-9.
Ref 533135Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes Metab. 2015 Apr;17(4):414-22.
Ref 534147J Med Chem. 1996 Jun 21;39(13):2449-55.Topographical amino acid substitution in position 10 of glucagon leads to antagonists/partial agonists with greater binding differences.
Ref 534773Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists. J Med Chem. 1998 Dec 17;41(26):5150-7.
Ref 536409Glucagon receptor expression and glucagon stimulation of ghrelin secretion in rat stomach. Biochem Biophys Res Commun. 2007 Jun 15;357(4):865-70. Epub 2007 Apr 9.
Ref 537009Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys. J Pharmacol Exp Ther. 2009 Apr;329(1):102-11. Epub 2009 Jan 7.
Ref 543641(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. (Target id: 251).
Ref 544477Addressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development. Curr Diabetes Rev. 2015 March; 11(1): 17-31.
Ref 547690Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018428)
Ref 550160WO patent application no. 2012,0351,39, Prodrugs comprising an exendin linker conjugate.
Ref 551054Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2009).
Ref 551494Clinical pipeline report, company report or official report of pfizer.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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