Identification

Name
Cholecystokinin
Accession Number
DB08862
Type
Small Molecule
Groups
Approved, Investigational
Description

Cholecystokinin ( also known as CCK or CCK-PZ) is a peptide hormone of the gastrointestinal system which is responsible for stimulating the digestion of fat and protein. Cholecystokinin, previously called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum (the first portion of the small intestine) and leads to the release of bile and digestive enzymes. CCK also acts as an appetite suppressant and has been studied for weight management regimens [12].

Normally, it is an endogenous hormone but is available commercially for diagnostic processes and replacement in pancreatic insufficiency [21, 22, 23]. in the octapeptide form.

Cholecystokinin is one of the first gastrointestinal hormones discovered, identified more than 90 years ago due to its ability to stimulate gallbladder contraction in 1928. Soon after, it was recognized to be identical to the factor responsible for stimulating pancreatic exocrine secretion in 1943 [11]. This hormone has also been shown to have positive effects on enteric smooth muscle contraction and on nerve activity at multiple locations in the peripheral and central nervous system. In addition to its roles in promoting smooth muscle cell contraction/exocrine cell secretion, CCK promotes cell growth, energy production, gene expression and protein synthesis, processes that have profound for drug development [11]. This drug has also been investigated for possible antipsychotic properties, owing to its effect on CCK receptors in the brain [13].

Recent studies have suggested that cholecystokinin also plays a major role in inducing drug tolerance to opioids such as morphine and heroin, and is partially implicated in experiences of pain hypersensitivity during opioid withdrawal [1].

Synonyms
  • CCK-PZ
  • Human CCK-33
  • Human cholecystokinin-33
  • Pancreozymin
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cholecystokinin Inj 75unit/vialPowder, for solution75 unitIntravenousFerring Pharmaceuticals1990-12-311999-08-04Canada
Categories
UNII
00XI8W60QF
CAS number
9011-97-6
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

For use as a diagnostic aid for evaluation of gallbladder disorders. It is also used in conjunction with secretin in pancreatic insufficiency [9].

Pharmacodynamics

Cholecystokinin (CCK) plays an imperative role in facilitating digestion within the small intestine. The activation of the CCK1 receptor by CCK has demonstrated to be responsible for a wide variety of important physiologic functions, including the stimulation of gallbladder, contraction and exocrine pancreatic enzyme secretion, delay of gastric emptying, relaxation of the sphincter of Oddi, inhibition of gastric acid secretion, and induction of satiety [7, 22]. Cholecystokinin is also produced by neurons in the enteric nervous system and is found to be widely distributed in the brain [7]. An interesting function of CCK is the role it plays in stimulating the CCK receptor and subsequently regulating food consumption, which may prove to be a highly useful treatment for obesity [14]. Exogenous administration CCK has been widely studied [16].

Diseases resulting from excessive or deficient secretion of cholecystokinin are rare. Cholecystokinin deficiency has been described in humans as part of autoimmune polyglandular syndrome, characterized as a malabsorption syndrome clinically similar to pancreatic exocrine insufficiency. Additionally, there is increasing evidence that alterations in expression of cholecystokinin or its receptor within the brain may possibly play a role in the pathogenesis of various types of anxiety disorders and schizophrenia [7].

Foodstuffs flowing into the small intestine are mostly made up of large macromolecules (proteins, polysaccharides, and triglyceride) that require digestion into small molecules (amino acids, monosaccharides, fatty acids) in order to be absorbed. Digestive enzymes from the pancreas and bile salts from the liver (which are stored in the gallbladder) are necessary for digestion. Cholecystokinin is the primary stimulus for the release of pancreatic enzymes and bile secretion into the small intestine. Additionally, cholecystokinin, induces contraction of the gallbladder muscle, resulting in the reduction of gallbladder size and evacuation of bile [9].

Mechanism of action

Cholecystokinin (CCK) is a peptide hormone discovered in the small intestine. Together with secretin and gastrin, CCK constitutes the classical gut hormone triad. In addition to gallbladder contraction, CCK also regulates pancreatic enzyme secretion and growth, intestinal motility, satiety signaling and the inhibition of gastric acid secretion. CCK is, however, also a transmitter in central and intestinal neurons. Notably, CCK is the most ubiquitously found neuropeptide in the human brain. Owing to difficulties in developing accurate assays for the hormone, knowledge about CCK secretion in disease is limited. Available data indicate, however, that proCCK is expressed in certain malignant neuroendocrine tumors and sarcomas, whereas the secretion of CCK is affected in celiac disease and the eating disorder bulimia nervosa. Stimulation with exogenous CCK has proved this protein useful in diagnostic imaging of gallbladder and pancreatic diseases, as well as testing of medullary thyroid carcinomas [2, 6, 18].

Cholecystokinin, a natural polypeptide which is formed in the amine precursor uptake and decarboxylation (APUD) cells of the proximal mucosa of the small intestine, promotes contraction of the gallbladder muscle, resulting in the reduction of gallbladder size and the expression of bile [9]. Cholecystokinin stimulates secretion of pancreatic digestive enzymes and secretion from the glands of Brunner [9].

CCK is composed of a five amino acid sequence at the carboxyl terminus that is identical to that of gastrin. The carboxyl terminus confers the biologic activity of CCK; as a result, gastrin has CCK-mimicking activity and CCK has gastrin-mimicking activity. The amino acid sequence similarity has made the creation of assays for CCK cumbersome, due to the fact that antibodies specific for the biologically active portion the molecule often cross-react with gastrin. This hormone circulates in the blood at concentrations 10 to 100 times greater than that of CCK [14].

TargetActionsOrganism
UCholecystokinin receptor type A
agonist
Human
URAF proto-oncogene serine/threonine-protein kinase
agonist
Human
UMitogen-activated protein kinase 3Not AvailableHuman
UPro-epidermal growth factorNot AvailableHuman
UProtein kinase C beta type
agonist
Human
UGastrin/cholecystokinin type B receptor
agonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

2.5 min [17]

Clearance
Not Available
Toxicity

Ld 50 in rats : 2730 mg/kg (oral) [24].

Cholecystokinin has been associated with increased anxiety and panic attacks [5].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Romanelli L, Morrone LA, Amico MC, Palmery M, Tucci P, Valeri P: Inhibitory control of the acute mu-withdrawal response by indirectly activated adenosine A1 and kappa-opioid systems in the Guinea-pig ileum; reversal by cholecystokinin. Neurotoxicology. 2005 Oct;26(5):829-39. doi: 10.1016/j.neuro.2005.02.001. [PubMed:15894374]
  2. Rehfeld JF: Clinical endocrinology and metabolism. Cholecystokinin. Best Pract Res Clin Endocrinol Metab. 2004 Dec;18(4):569-86. doi: 10.1016/j.beem.2004.07.002. [PubMed:15533776]
  3. Williams JA: Mechanism of action of cholecystokinin: a not atypical brain-gut peptide. Nihon Naibunpi Gakkai Zasshi. 1985 May 20;61(5):533-40. [PubMed:2991034]
  4. Hoffmann P, Eberlein GA, Reeve JR Jr, Bunte RH, Grandt D, Goebell H, Eysselein VE: Comparison of clearance and metabolism of infused cholecystokinins 8 and 58 in dogs. Gastroenterology. 1993 Dec;105(6):1732-6. [PubMed:8253350]
  5. Bradwejn J, Koszycki D: Cholecystokinin and panic disorder: past and future clinical research strategies. Scand J Clin Lab Invest Suppl. 2001;234:19-27. [PubMed:11713976]
  6. Kwekkeboom DJ, Bakker WH, Kooij PP, Erion J, Srinivasan A, de Jong M, Reubi JC, Krenning EP: Cholecystokinin receptor imaging using an octapeptide DTPA-CCK analogue in patients with medullary thyroid carcinoma. Eur J Nucl Med. 2000 Sep;27(9):1312-7. [PubMed:11007512]
  7. cholecystokinin [Link]
  8. Cholecystokinin metabolism in man and dogs [Link]
  9. Cholecystokinin [Link]
  10. Cholecystokinin- a review [Link]
  11. Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor [Link]
  12. Cholecystokinin receptors in brain: Effects of obesity, drug treatment, and lesions Author links open overlay panel [Link]
  13. SR146131, a cholecystokinin-A receptor agonist, antagonizes prepulse inhibition deficits produced by dizocilpine and DOI [Link]
  14. Physiology of CCK [Link]
  15. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
  16. Effect of Exogenous Cholecystokinin (CCK)-8 on Food Intake and Plasma CCK, Leptin, and Insulin Concentrations in Older and Young Adults: Evidence for Increased CCK Activity as a Cause of the Anorexia of Aging [Link]
  17. Comparison of Gallbladder Function Obtained with Regular CCK-8 and Pharmacy-Compounded CCK-8 [Link]
  18. Bioactivity of synthetic human cholecystokinin (CCK)-33 in vitro and in vivo [Link]
  19. Cholecystokinin Octapeptide [Link]
  20. Cholecystokinin Octapeptide, [125I]-, Bolton-Hunter Labeled, 10µCi [Link]
  21. Alfa Aesar™ Cholecystokinin, CCK Octapeptide (26-33) [Link]
  22. Cholecystokinin-Pancreozymin Peptides Products [Link]
  23. CCK Octapeptide sulfated [Link]
  24. Cholecystokinin Octapeptide [Link]
External Links
PubChem Substance
347910375
Wikipedia
Cholecystokinin
ATC Codes
V04CK02 — Pancreozymin (cholecystokinin)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentType 2 Diabetes Mellitus1
Not AvailableCompletedBasic ScienceType 2 Diabetes Mellitus2
Not AvailableRecruitingDiagnosticAbdominal Pain (AP)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous75 unit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)75http://www.perkinelmer.com/Content/MSDSDatabase/CHOLECYSTOKININ%20OCTAPEPTIDE%20125I-BOLTON-HUNTER%20LABELED%20ASP1%20CCK-8-MSDS_US-English.pdf
water solubilitynot water solublehttp://www.perkinelmer.com/Content/MSDSDatabase/CHOLECYSTOKININ%20OCTAPEPTIDE%20125I-BOLTON-HUNTER%20LABELED%20ASP1%20CCK-8-MSDS_US-English.pdf
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Peptide binding
Specific Function
Receptor for cholecystokinin. 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 gas...
Gene Name
CCKAR
Uniprot ID
P32238
Uniprot Name
Cholecystokinin receptor type A
Molecular Weight
47840.645 Da
References
  1. Williams JA: Mechanism of action of cholecystokinin: a not atypical brain-gut peptide. Nihon Naibunpi Gakkai Zasshi. 1985 May 20;61(5):533-40. [PubMed:2991034]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determin...
Gene Name
RAF1
Uniprot ID
P04049
Uniprot Name
RAF proto-oncogene serine/threonine-protein kinase
Molecular Weight
73051.025 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Phosphatase binding
Specific Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK ca...
Gene Name
MAPK3
Uniprot ID
P27361
Uniprot Name
Mitogen-activated protein kinase 3
Molecular Weight
43135.16 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transmembrane receptor protein tyrosine kinase activator activity
Specific Function
EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in ...
Gene Name
EGF
Uniprot ID
P01133
Uniprot Name
Pro-epidermal growth factor
Molecular Weight
133993.12 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosom...
Gene Name
PRKCB
Uniprot ID
P05771
Uniprot Name
Protein kinase C beta type
Molecular Weight
76868.45 Da
References
  1. Cholecystokinin stimulates extracellular signal-regulated kinase through activation of the epidermal growth factor receptor, Yes, and protein kinase C. Signal amplification at the level of Raf by activation of protein kinase Cepsilon. [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Type b gastrin/cholecystokinin receptor binding
Specific Function
Receptor for gastrin and cholecystokinin. The CKK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor me...
Gene Name
CCKBR
Uniprot ID
P32239
Uniprot Name
Gastrin/cholecystokinin type B receptor
Molecular Weight
48418.51 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Ismair MG, Stieger B, Cattori V, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA: Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology. 2001 Nov;121(5):1185-90. [PubMed:11677211]

Drug created on March 03, 2013 17:52 / Updated on June 02, 2018 08:13