Target Information

Target General Information

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Target ID

T28330 (Former ID: TTDC00082)

Target Name

Cholecystokinin receptor type A (CCKAR)

Synonyms

CCKAR; CCK-AR; CCK-A receptor

Gene Name

CCKAR

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Influenza [ICD-11: 1E30-1E32]

Pancreatic malfunction [ICD-11: DC30-DC3Z]

Function

Receptor forcholecystokinin. Mediates pancreatic growth and enzyme secretion, smooth muscle contraction of the gall bladder and stomach. Has a 1000-fold higher affinity for CCK rather than for gastrin. It modulates feeding and dopamine-induced behavior in the central and peripheral nervous system. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.

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BioChemical Class

GPCR rhodopsin

UniProt ID

CCKAR_HUMAN

Sequence

MDVVDSLLVNGSNITPPCELGLENETLFCLDQPRPSKEWQPAVQILLYSLIFLLSVLGNT
LVITVLIRNKRMRTVTNIFLLSLAVSDLMLCLFCMPFNLIPNLLKDFIFGSAVCKTTTYF
MGTSVSVSTFNLVAISLERYGAICKPLQSRVWQTKSHALKVIAATWCLSFTIMTPYPIYS
NLVPFTKNNNQTANMCRFLLPNDVMQQSWHTFLLLILFLIPGIVMMVAYGLISLELYQGI
KFEASQKKSAKERKPSTTSSGKYEDSDGCYLQKTRPPRKLELRQLSTGSSSRANRIRSNS
SAANLMAKKRVIRMLIVIVVLFFLCWMPIFSANAWRAYDTASAERRLSGTPISFILLLSY
TSSCVNPIIYCFMNKRFRLGFMATFPCCPNPGPPGARGEVGEEEEGGTTGASLSRFSYSH
MSASVPPQ

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

Dexloxiglumide

Drug Info

Phase 2

Pancreatic malfunction

[2]

proglumide

Drug Info

Phase 2

Influenza virus infection

[3]

Discontinued Drug(s)

[+] 15 Discontinued Drugs

CE-326597

Drug Info

Discontinued in Phase 2

Obesity

[4]

GI 181771

Drug Info

Discontinued in Phase 2

Obesity

[5]

Lintitript

Drug Info

Discontinued in Phase 2

Obesity

[6], [7]

Pranazepide

Drug Info

Discontinued in Phase 2

Pancreatic malfunction

[8], [9]

Tarazepide

Drug Info

Discontinued in Phase 2

Gastrointestinal disease

[10]

SR-146131

Drug Info

Discontinued in Phase 1

Obesity

[11], [12]

SSR-125180

Drug Info

Discontinued in Phase 1

Obesity

[13]

T-0632

Drug Info

Discontinued in Phase 1

Pancreatic malfunction

[14], [15]

UCL-2000; butabindide

Drug Info

Discontinued in Phase 1

Obesity

[16]

A-70276

Drug Info

Terminated

Gastrointestinal disease

[19]

A-71623

Drug Info

Terminated

Obesity

[20], [21]

FR-208419

Drug Info

Terminated

Dyspepsia

[22]

GI-248573

Drug Info

Terminated

Bladder disease

[23]

Lorglumide

Drug Info

Terminated

Pancreatic malfunction

[24], [25]

SR-27950

Drug Info

Terminated

Eating disorder

[26]

Preclinical Drug(s)

[+] 6 Preclinical Drugs

A-71378

Drug Info

Preclinical

Obesity

[17], [18]

A-74498

Drug Info

Preclinical

Obesity

[18]

AR-R-1589

Drug Info

Preclinical

Eating disorder

[18]

FPL-14294

Drug Info

Preclinical

Obesity

[18]

GG-8573

Drug Info

Preclinical

Obesity

[18]

PD-170292

Drug Info

Preclinical

Obesity

[18]

Mode of Action

[+] 4 Modes of Action

Inhibitor

[+] 51 Inhibitor drugs

Dexloxiglumide

Drug Info

[27]

Pranazepide

Drug Info

[32]

CR-1795

Drug Info

[41]

IQM-95333

Drug Info

[43]

PD-135666

Drug Info

[45]

SNF-9007

Drug Info

[46]

1-(3,3-Diphenyl-allyl)-3-m-tolyl-urea

Drug Info

[48]

1-(4-Chloro-phenyl)-3-(3,3-diphenyl-allyl)-urea

Drug Info

[48]

1-(4-Chloro-phenyl)-3-(3-pentyl-oct-2-enyl)-urea

Drug Info

[48]

3,4-Dichloro-N-(3,3-diphenyl-allyl)-benzamide

Drug Info

[48]

Asp-Tyr(OSO3H)-Met-Gly-Trp-Met-Asp-Phe

Drug Info

[50]

Boc-Asp-Tyr(So3-)-Nle-Gly-Trp-Asp-Phe-NH2

Drug Info

[53]

Boc-cyclo-(Glu-Tyr-Nle-D-Lys)-Trp-Nle-Asp-Phe-NH2

Drug Info

[54]

Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2

Drug Info

[54]

Boc-D-Glu-Tyr(SO3H)-Nle-D-Nle-Trp-Nle-Asp-Phe-NH2

Drug Info

[54]

Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2

Drug Info

[54]

Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2

Drug Info

[54]

CR-2345

Drug Info

[41]

FR-175985

Drug Info

[32]

H-Tyr-D-Ala-Gly-Phe-NH-NH-D-Trp-Nle-Asp-Phe-H

Drug Info

[60]

H-Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Asp-Nle-D-Trp-H

Drug Info

[61]

H-Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Asp-Nle-Trp-Boc

Drug Info

[61]

H-Tyr-D-Ala-Gly-Phe-NH-NH-Trp-D-Nle-D-Asp-D-Phe-H

Drug Info

[60]

L-708474

Drug Info

[66]

L-740093

Drug Info

[68]

PD-135118

Drug Info

[45]

PD-136621

Drug Info

[45]

PD-137337

Drug Info

[45]

PD-137342

Drug Info

[45]

PD-138915

Drug Info

[45]

PD-138916

Drug Info

[45]

PD-140547

Drug Info

[45]

PD-140548

Drug Info

[45]

PD-140723

Drug Info

[45]

Tetragastrin

Drug Info

[69]

Tyr-D-Ala-Gly-D-Trp-Nle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Ala-Gly-D-Trp-NMeNle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Asp-NMeNle-D-Trp-Boc

Drug Info

[61]

Tyr-D-Ala-Gly-Trp-Nle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Ala-Gly-Trp-NMeNle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Nle-Gly-D-Trp-NMeNle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Nle-Gly-Trp-Nle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Phe-Gly-D-Trp-Nle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Phe-Gly-D-Trp-NMeNle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Phe-Gly-Trp-Nle-Asp-Phe-NH2

Drug Info

[46]

Tyr-D-Phe-Gly-Trp-NMeNle-Asp-Phe-NH2

Drug Info

[46]

VL-0395

Drug Info

[71]

VL-0494

Drug Info

[72]

VL-0699

Drug Info

[73]

VL-1499

Drug Info

[71]

VL-2799

Drug Info

[74]

Antagonist

[+] 18 Antagonist drugs

proglumide

Drug Info

[1]

Lintitript

Drug Info

[30], [31]

Tarazepide

Drug Info

[33], [34], [35]

T-0632

Drug Info

[38]

Lorglumide

Drug Info

[44]

2-NAP

Drug Info

[49]

Asperlicin

Drug Info

[51]

Bis(31/31')[[Cys(31), Nva(34)]NPY(27-36)-NH(2)]

Drug Info

[52]

CI-1015

Drug Info

[57]

Devazepide

Drug Info

[51]

IQM-97423

Drug Info

[62]

JNJ-17156516

Drug Info

[64]

KSG-504

Drug Info

[65]

L-736380

Drug Info

[67]

PD-135158

Drug Info

[56]

SC-50998

Drug Info

[47]

TP-680

Drug Info

[70]

[3H]devazepide

Drug Info

[75]

Agonist

[+] 16 Agonist drugs

CE-326597

Drug Info

[28]

GI 181771

Drug Info

[29]

SR-146131

Drug Info

[36]

SSR-125180

Drug Info

[37]

UCL-2000; butabindide

Drug Info

[18]

A-71378

Drug Info

[18]

A-74498

Drug Info

[18]

AR-R-1589

Drug Info

[18]

FPL-14294

Drug Info

[18]

GG-8573

Drug Info

[18]

PD-170292

Drug Info

[18]

CCK-33

Drug Info

[55]

CCK-8

Drug Info

[56]

Glaxo-11p

Drug Info

[58]

GW-5823

Drug Info

[59]

JMV180

Drug Info

[63]

Modulator

[+] 5 Modulator drugs

A-70276

Drug Info

[39]

A-71623

Drug Info

[40]

FR-208419

Drug Info

[42]

GI-248573

Drug Info

[37]

SR-27950

Drug Info

[47]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 4 KEGG Pathways

Calcium signaling pathway

Neuroactive ligand-receptor interaction

Insulin secretion

Pancreatic secretion

Reactome

[+] 2 Reactome Pathways

Peptide ligand-binding receptors

G alpha (q) signalling events

WikiPathways

[+] 5 WikiPathways

GPCRs, Class A Rhodopsin-like

Gastrin-CREB signalling pathway via PKC and MAPK

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists. Arzneimittelforschung. 1987 Nov;37(11):1265-8.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

ClinicalTrials.gov (NCT00542009) A Trial In Diabetic Patients To Assess Effect Of CE-326,597 On Glucose Control And Body Weight. U.S. National Institutes of Health.

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013294)

REF 6

URL: 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: 890).

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004912)

REF 8

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003071)

REF 10

Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence. BMC Neurosci. 2012 Jun 8;13:63.

REF 11

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010439)

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015967)

REF 14

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007781)

REF 16

Clinical pipeline report, company report or official report of University College London.

REF 17

REF 18

Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003433)

REF 20

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003438)

REF 22

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010485)

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008844)

REF 24

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000580)

REF 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001260)

REF 27

Full agonists of CCK8 containing a nonhydrolyzable sulfated tyrosine residue. J Med Chem. 1989 Feb;32(2):445-9.

REF 28

Obesity Pharmacotherapy: Current Perspectives and Future Directions. Curr Cardiol Rev. 2013 February; 9(1): 33-54.

REF 29

Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003 Jul-Aug;25(6):483-506.

REF 30

A cholecystokinin-1 receptor agonist (CCK-8) mediates increased permeability of brain barriers to leptin. Br J Pharmacol. 2008 Jul;154(5):1009-15.

REF 31

A novel role for cholecystokinin: regulation of mesenteric vascular resistance. Regul Pept. 2004 Sep 15;121(1-3):145-53.

REF 32

Dual CCK-A and -B receptor antagonists (I) C9-methyl-1,4-benzodiazepines, Bioorg. Med. Chem. Lett. 7(2):169-174 (1997).

REF 33

Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector. J Physiol Pharmacol. 2007 Dec;58 Suppl 6:65-80.

REF 34

The ghrelin pentapeptide inhibits the secretion of pancreatic juice in rats. J Physiol Pharmacol. 2006 Dec;57(4):691-700.

REF 35

Effects of intraduodenal administration of tarazepide on pancreatic secretion and duodenal EMG in neonatal calves. Regul Pept. 1998 Nov 30;78(1-3):113-23.

REF 36

SR146131: a new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. I. In vitro studies. J Pharmacol Exp Ther. 1999 May;289(2):742-51.

REF 37

US patent application no. 8,748,419, Antagonists.

REF 38

Effect of T-0632, a cholecystokininA receptor antagonist, on experimental acute pancreatitis. Jpn J Pharmacol. 1997 Feb;73(2):105-12.

REF 39

Cholecystokinin antagonists: (R)-tryptophan-based hybrid antagonists of high affinity and selectivity for CCK-A receptors. J Med Chem. 1991 Dec;34(12):3350-9.

REF 40

Characterization of two novel cholecystokinin tetrapeptide (30-33) analogues, A-71623 and A-70874, that exhibit high potency and selectivity for cholecystokinin-A receptors. Mol Pharmacol. 1991 Mar;39(3):346-51.

REF 41

Biological properties of (R)-4-benzamido-5-oxopentanoic basic derivatives as CCK-antagonists, Bioorg. Med. Chem. Lett. 3(5):861-866 (1993).

REF 42

Dual CCK-A and CCK-B receptor antagonists (II). Preparation and structure activity relationships of 5-alkyl-9-methyl-1,4-benzodiazepines and discovery of FR208419. Chem Pharm Bull (Tokyo). 2000 Jan;48(1):1-15.

REF 43

Synthesis and stereochemical structure-activity relationships of 1,3-dioxoperhydropyrido[1,2-c]pyrimidine derivatives: potent and selective cholecy... J Med Chem. 1997 Oct 10;40(21):3402-7.

REF 44

Behavioral and neurochemical study on the role of the brain cholecystokinin system in anxiety. Hokkaido Igaku Zasshi. 1998 Sep;73(5):463-73.

REF 45

Selective ligands for cholecystokinin receptor subtypes CCK-A and CCK-B within a single structural class, Bioorg. Med. Chem. Lett. 3(5):881-884 (1993).

REF 46

Structure-activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. J Med Chem. 2006 May 18;49(10):2868-75.

REF 47

REF 48

Hybrid cholecystokinin-A antagonists based on molecular modeling of lorglumide and L-364,718. J Med Chem. 1992 Mar 20;35(6):1042-9.

REF 49

Unexpected relationship between plasma protein binding and the pharmacodynamics of 2-NAP, a CCK1-receptor antagonist. Br J Clin Pharmacol. 2007 May;63(5):618-22.

REF 50

Toward developing peptidomimetics: Successful replacement of backbone amide bonds in tetrapeptide-based CCK-A receptor agonists, Bioorg. Med. Chem. Lett. 3(5):855-860 (1993).

REF 51

Privileged structures: a useful concept for the rational design of new lead drug candidates. Mini Rev Med Chem. 2007 Nov;7(11):1108-19.

REF 52

Role of CCK(A) receptors in postprandial lower esophageal sphincter function in morbidly obese subjects. Dig Dis Sci. 2002 Nov;47(11):2531-7.

REF 53

Synthesis and biological activities of pseudopeptide analogues of the C-terminal heptapeptide of cholecystokinin. On the importance of the peptide ... J Med Chem. 1987 Aug;30(8):1366-73.

REF 54

Synthesis and binding affinities of cyclic and related linear analogues of CCK8 selective for central receptors. J Med Chem. 1989 Jun;32(6):1184-90.

REF 55

Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6917-21.

REF 56

Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728-32.

REF 57

Second generation "peptoid" CCK-B receptor antagonists: identification and development of N-(adamantyloxycarbonyl)-alpha-methyl-(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile. J Med Chem. 1998 Jan 1;41(1):38-45.

REF 58

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger". J Med Chem. 1996 Jan 19;39(2):562-9.

REF 59

Optimization of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepines as potent, orally active CCK-A agonists. J Med Chem. 1997 Aug 15;40(17):2706-25.

REF 60

Partial retro-inverso, retro, and inverso modifications of hydrazide linked bifunctional peptides for opioid and cholecystokinin (CCK) receptors. J Med Chem. 2007 Jan 11;50(1):165-8.

REF 61

Design and synthesis of novel hydrazide-linked bifunctional peptides as delta/mu opioid receptor agonists and CCK-1/CCK-2 receptor antagonists. J Med Chem. 2006 Mar 9;49(5):1773-80.

REF 62

Pharmacological study of IQM-97,423, a potent and selective CCK1 receptor antagonist with protective effect in experimental acute pancreatitis. Pharmacology. 2004 Oct;72(2):68-76.

REF 63

Identification of a region of the N-terminal of the human CCKA receptor essential for the high affinity interaction with agonist CCK. Biochem Biophys Res Commun. 1995 Aug 24;213(3):845-52.

REF 64

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a novel, potent, and selective cholecystokini... J Pharmacol Exp Ther. 2007 Nov;323(2):562-9.

REF 65

Effects of KSG-504, a new CCK-A receptor antagonist, on gallbladder and gastrointestinal functions. Nihon Yakurigaku Zasshi. 1996 Jan;107(1):33-44.

REF 66

High-affinity and potent, water-soluble 5-amino-1,4-benzodiazepine CCKB/gastrin receptor antagonists containing a cationic solubilizing group. J Med Chem. 1994 Mar 18;37(6):719-21.

REF 67

Controlled modification of acidity in cholecystokinin B receptor antagonists: N-(1,4-benzodiazepin-3-yl)-N'-[3-(tetrazol-5-ylamino) phenyl]ureas. J Med Chem. 1996 Feb 16;39(4):842-9.

REF 68

C5-piperazinyl-1,4-benzodiazepines, water-soluble, orally bioa vailable CCKB/gastrin receptor antagonists, Bioorg. Med. Chem. Lett. 5(24):3023-3026 (1995).

REF 69

Synthesis and binding affinities of analogues of cholecystokinin-(30-33) as probes for central nervous system cholecystokinin receptors. J Med Chem. 1987 Apr;30(4):729-32.

REF 70

Pharmacological profile of TP-680, a new cholecystokininA receptor antagonist. Br J Pharmacol. 1996 Apr;117(7):1558-64.

REF 71

2D-QSAR and 3D-QSAR/CoMFA analyses of the N-terminal substituted anthranilic acid based CCK(1) receptor antagonists: 'Hic Rhodus, hic saltus'. Bioorg Med Chem. 2009 Jul 15;17(14):5198-206.

REF 72

Synthesis and evaluation of novel benzimidazole derivative [Bz-Im] and its radio/biological studies. Bioorg Med Chem Lett. 2007 May 15;17(10):2749-55.

REF 73

Anthranilic acid based CCK1 receptor antagonists and CCK-8 have a common step in their "receptor desmodynamic processes". J Med Chem. 2006 Apr 20;49(8):2456-62.

REF 74

Anthranilic acid based CCK1 receptor antagonists: blocking the receptor with the same 'words' of the endogenous ligand. Bioorg Med Chem. 2009 Mar 15;17(6):2336-50.

REF 75

Characterization of the binding of [3H]-(+/-)-L-364,718: a new potent, nonpeptide cholecystokinin antagonist radioligand selective for peripheral receptors. Mol Pharmacol. 1986 Sep;30(3):212-7.

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