Cholecystokinin antagonist
Encyclopedia
A Cholecystokinin antagonist is a specific type of receptor antagonist
which blocks the receptor sites for the peptide
hormone
Cholecystokinin
(CCK
).
There are two subtypes of this receptor known at present, defined as CCKA
and CCKB
(also called CCK-1 and CCK-2). CCKA is mainly expressed in the small intestine, and is involved in the regulation of enzyme secretion by the pancreas, secretion of gastric acid in the stomach, intestinal motility and signalling of satiety (fullness). CCKB is expressed mainly in the central nervous system, and has functions relating to anxiety and the perception of pain. Antagonists for the CCK receptors can thus have multiple functions in both the gut and brain.
The best known CCK antagonist is the non-selective antagonist proglumide
, which blocks both CCKA and CCKB, and was originally developed for the treatment of stomach ulcers. This action derived from its blockade of CCKA in the gut and consequent reduction in secretion of gastric acid, however an interesting side effect of proglumide was found, namely that it increases the analgesic effects of opioid painkillers, and decreases the development of tolerance. This was subsequently found to result from its blockade of CCKB receptors in the brain.
Newer drugs have since been developed which are selective for one or other of the CCK receptors. Selective CCKA antagonists such as lorglumide
and devazepide
have been developed both for their anti-ulcer effects and as potential drugs to limit the development of gastrointestinal cancers such as colon cancer.
However by far the main focus of CCK antagonist research has focused on the development of selective CCKB antagonists as novel medications which have been primarily investigated for the treatment of anxiety and panic attacks, as well as for other roles such as analgesic effects. The first selective CCKB antagonists were modified peptide molecules such as CI-988
and the more metabolically stable CI-1015, however these were disadvantaged by only being able to be administered by injection and rapid breakdown inside the body, which led to a short half-life and limited utility. Non-peptide CCKB antagonists such as L-365,260, L-369,293, YF-476, RP-69758, LY-288,513, PD-145,942 and the CCKB inverse agonist L-740,093 have since been developed, and while all of the drugs developed so far have suffered from limited bioavailability or other issues which have hindered their clinical development, research in this area continues.
CCKA receptors are also expressed in the brain to some extent, and interestingly IQM-95333, an antagonist selective for this population of CCKA receptors, was also found to reduce anxiety in animal models. Conversely, inhibition of CCKB receptors in the gut produces similar inhibition of secretion of gastric acid and pepsinogen enzymes as is seen with inhibition of CCKA receptors, suggesting that while the CCKA and CCKB receptors comprise two structurally distinct families which bind different ligands and are primarily expressed in different tissues, they produce similar effects, and the distinction between their gastrointestinal and anxiolytic actions depends mainly on where they are expressed in the body.
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
which blocks the receptor sites for the peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
Cholecystokinin
Cholecystokinin
Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein...
(CCK
Cholecystokinin receptor
Cholecystokinin receptors or CCK receptors are a group of G-protein coupled receptors which bind the peptide hormones cholecystokinin or gastrin...
).
There are two subtypes of this receptor known at present, defined as CCKA
Cholecystokinin A receptor
The extracellular, N-terminal, domain of this protein adopts a tertiary structure consisting of a few helical turns and a disulfide-cross linked loop...
and CCKB
Cholecystokinin B receptor
The cholecystokinin B receptor also known as CCKBR or CCK2 is a protein that in humans is encoded by the CCKBR gene.This gene encodes a G protein-coupled receptor for gastrin and cholecystokinin , regulatory peptides of the brain and gastrointestinal tract...
(also called CCK-1 and CCK-2). CCKA is mainly expressed in the small intestine, and is involved in the regulation of enzyme secretion by the pancreas, secretion of gastric acid in the stomach, intestinal motility and signalling of satiety (fullness). CCKB is expressed mainly in the central nervous system, and has functions relating to anxiety and the perception of pain. Antagonists for the CCK receptors can thus have multiple functions in both the gut and brain.
The best known CCK antagonist is the non-selective antagonist proglumide
Proglumide
Proglumide is a drug that inhibits gastrointestinal motility and reduces gastric secretions. It acts as a cholecystokinin antagonist, which blocks both the CCKA and CCKB subtypes...
, which blocks both CCKA and CCKB, and was originally developed for the treatment of stomach ulcers. This action derived from its blockade of CCKA in the gut and consequent reduction in secretion of gastric acid, however an interesting side effect of proglumide was found, namely that it increases the analgesic effects of opioid painkillers, and decreases the development of tolerance. This was subsequently found to result from its blockade of CCKB receptors in the brain.
Newer drugs have since been developed which are selective for one or other of the CCK receptors. Selective CCKA antagonists such as lorglumide
Lorglumide
Lorglumide is a drug which inhibits gastrointestinal motility and reduces gastric secretions, acting as a cholecystokinin antagonist, with fairly high selectivity for the CCKA subtype...
and devazepide
Devazepide
Devazepide is a drug which is structurally derived from the benzodiazepine family, but with quite different actions from most benzodiazepines, lacking affinity for GABAA receptors and instead acting as a cholecystokinin antagonist selective for the CCKA subtype...
have been developed both for their anti-ulcer effects and as potential drugs to limit the development of gastrointestinal cancers such as colon cancer.
However by far the main focus of CCK antagonist research has focused on the development of selective CCKB antagonists as novel medications which have been primarily investigated for the treatment of anxiety and panic attacks, as well as for other roles such as analgesic effects. The first selective CCKB antagonists were modified peptide molecules such as CI-988
CI-988
CI-988 is a drug which acts as a cholecystokinin antagonist, selective for the CCKB subtype. In animal studies it showed anxiolytic effects and potentiated the analgesic action of both morphine and endogenous opioid peptides, as well as preventing the development of tolerance to opioids and...
and the more metabolically stable CI-1015, however these were disadvantaged by only being able to be administered by injection and rapid breakdown inside the body, which led to a short half-life and limited utility. Non-peptide CCKB antagonists such as L-365,260, L-369,293, YF-476, RP-69758, LY-288,513, PD-145,942 and the CCKB inverse agonist L-740,093 have since been developed, and while all of the drugs developed so far have suffered from limited bioavailability or other issues which have hindered their clinical development, research in this area continues.
CCKA receptors are also expressed in the brain to some extent, and interestingly IQM-95333, an antagonist selective for this population of CCKA receptors, was also found to reduce anxiety in animal models. Conversely, inhibition of CCKB receptors in the gut produces similar inhibition of secretion of gastric acid and pepsinogen enzymes as is seen with inhibition of CCKA receptors, suggesting that while the CCKA and CCKB receptors comprise two structurally distinct families which bind different ligands and are primarily expressed in different tissues, they produce similar effects, and the distinction between their gastrointestinal and anxiolytic actions depends mainly on where they are expressed in the body.