Cholecystokinin antagonist

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A cholecystokinin receptor 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). The CCKA receptor 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 signaling of satiety (fullness). The CCKB receptor is expressed mainly in the central nervous system, and has functions relating to anxiety and the perception of pain. [1] Antagonists for the CCK receptors can thus have multiple functions in both the gut and brain.

The best known CCK receptor antagonist is the non-selective antagonist proglumide, which blocks both CCKA and CCKB receptors, and was originally developed for the treatment of stomach ulcers. This action derived from its blockade of CCKA receptor in the gut and consequent reduction in secretion of gastric acid, however a 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. Another CCK receptor antagonist is benzotript, which is likewise non-selective.

Newer drugs have since been developed which are selective for one or other of the CCK receptors. Selective CCKA receptor 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. [2]

However by far the main focus of CCK receptor antagonist research has focused on the development of selective CCKB receptor 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 receptor 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 receptor antagonists such as L-365,260, L-369,293, YF-476, RP-69758, LY-288,513, PD-145,942 and the CCKB receptor inverse agonist L-740,093 have since been developed, [3] 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. [4]

CCKA receptors are also expressed in the brain to some extent, and IQM-95333, an antagonist selective for this population of CCKA receptors, was also found to reduce anxiety in animal models. [5] 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, [6] 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.

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Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, formerly called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum, the first segment of the small intestine. Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively..

<span class="mw-page-title-main">Gastrin</span> Mammalian protein found in Homo sapiens

Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.

<span class="mw-page-title-main">Imidazopyridine</span> Class of compounds

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Cholecystokinin receptors or CCK receptors are a group of G-protein coupled receptors which bind the peptide hormones cholecystokinin (CCK) and gastrin. There are two different subtypes CCKA and CCKB which are ~50% homologous: Various cholecystokinin antagonists have been developed and are used in research, although the only drug of this class that has been widely marketed to date is the anti-ulcer drug proglumide.

<span class="mw-page-title-main">Vasoactive intestinal peptide</span> Hormone that affects blood pressure / heart rate

Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, cortex, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gallbladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.

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<span class="mw-page-title-main">Enteroendocrine cell</span> Cell that produces gastrointestinal hormones

Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.

<span class="mw-page-title-main">Cholecystokinin B receptor</span> Protein-coding gene in the species Homo sapiens

The cholecystokinin B receptor also known as CCKBR or CCK2 is a protein that in humans is encoded by the CCKBR gene.

<span class="mw-page-title-main">Cholecystokinin A receptor</span> Protein-coding gene in the species Homo sapiens

The Cholecystokinin A receptor is a human protein, also known as CCKAR or CCK1, with CCK1 now being the IUPHAR-recommended name.

<span class="mw-page-title-main">Proglumide</span> Chemical compound

Proglumide, sold under the brand name Milid, 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. It was used mainly in the treatment of stomach ulcers, although it has now been largely replaced by newer drugs for this application.

Prostaglandin EP<sub>3</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin EP3 receptor (EP3, 53kDa), is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

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<span class="mw-page-title-main">RB-101</span> Chemical compound

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<span class="mw-page-title-main">CCK-4</span> Anxiogenic agent

Cholecystokinin tetrapeptide (CCK-4, tetragastrin, Trp-Met-Asp-Phe-NH2) is a peptide fragment derived from the larger peptide hormone cholecystokinin. Unlike cholecystokin which has a variety of roles in the gastrointestinal system as well as central nervous system effects, CCK-4 acts primarily in the brain as an anxiogenic, although it does retain some GI effects, but not as much as CCK-8 or the full length polypeptide CCK-58.

<span class="mw-page-title-main">Lorglumide</span> Chemical compound

Lorglumide (CR-1409) is a drug which inhibits gastrointestinal motility and reduces gastric secretions, acting as a cholecystokinin antagonist, with fairly high selectivity for the CCKA subtype. It has been suggested as a potential treatment for a variety of gastrointestinal problems including stomach ulcers, irritable bowel syndrome, dyspepsia, constipation and pancreatitis, as well as some forms of cancer, but animal and human testing has produced inconsistent results and no clear therapeutic role has been established, although it is widely used in scientific research.

<span class="mw-page-title-main">Devazepide</span> Chemical compound

Devazepide is benzodiazepine drug, but with quite different actions from most benzodiazepines, lacking affinity for GABAA receptors and instead acting as an CCKA receptor antagonist. It increases appetite and accelerates gastric emptying, and has been suggested as a potential treatment for a variety of gastrointestinal problems including dyspepsia, gastroparesis and gastric reflux. It is also widely used in scientific research into the CCKA receptor.

<span class="mw-page-title-main">Dexloxiglumide</span> Chemical compound

Dexloxiglumide is a drug which acts as a cholecystokinin antagonist, selective for the CCKA subtype. It inhibits gastrointestinal motility and reduces gastric secretions, and despite older selective CCKA antagonists such as lorglumide and devazepide having had only limited success in trials and ultimately never making it into clinical use, dexloxiglumide is being investigated as a potential treatment for a variety of gastrointestinal problems including irritable bowel syndrome, dyspepsia, constipation and pancreatitis, and has had moderate success so far although trials are still ongoing.

<span class="mw-page-title-main">CI-988</span> Chemical compound

CI-988 (PD-134,308) 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 reducing symptoms of withdrawal. Consequently, it was hoped that it might have clinical applications for the treatment of pain and anxiety in humans, but trial results were disappointing with only minimal therapeutic effects observed even at high doses. The reason for the failure of CI-988 and other CCKB antagonists in humans despite their apparent promise in pre-clinical animal studies is unclear, although poor pharmacokinetic properties of the currently available drugs are a possible explanation, and CCKB antagonists are still being researched for possible uses as adjuvants to boost the activity of other drugs.

<span class="mw-page-title-main">Benzotript</span> Cholecystokinin antagonist

Benzotript (INNTooltip International Nonproprietary Name), also known as N-(p-chlorobenzoyl)-L-tryptophan, is a muscle relaxant that inhibits gastric secretion and was never marketed. It is a tryptamine derivative and the N-(4-chlorobenzoyl) analogue of the amino acid tryptophan. Similarly to proglumide (N2-benzoyl-N,N-dipropyl-α-glutamine), the drug acts as a competitive and non-selective cholecystokinin receptor antagonist. Other more potent tryptophan derivatives have also been developed as cholecystokinin (CCK) antagonists.

References

  1. ↑ Rehfeld, JF (2004). "Clinical endocrinology and metabolism. Cholecystokinin". Best Practice & Research. Clinical Endocrinology & Metabolism. 18 (4): 569–86. doi:10.1016/j.beem.2004.07.002. PMID   15533776.
  2. ↑ González-Puga, C; García-Navarro, A; Escames, G; León, J; López-Cantarero, M; Ros, E; Acuña-Castroviejo, D (2005). "Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin". Journal of Pineal Research. 39 (3): 243–50. doi:10.1111/j.1600-079X.2005.00239.x. PMID   16150104. S2CID   20187767.
  3. ↑ Noble, F; Roques, BP (1999). "CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology". Progress in Neurobiology. 58 (4): 349–79. doi:10.1016/S0301-0082(98)00090-2. PMID   10368033. S2CID   24402373.
  4. ↑ Kalindjian, SB; Mcdonald, IM (2007). "Strategies for the design of non-peptide CCK2 receptor agonist and antagonist ligand". Current Topics in Medicinal Chemistry. 7 (12): 1195–204. doi:10.2174/156802607780960500. PMID   17584141.
  5. ↑ Ballaz, S; Barber, A; Fortuño, A; Del Río, J; Martin-Martínez, M; Gómez-Monterrey, I; Herranz, R; González-Muñiz, R; García-López, MT (1997). "Pharmacological evaluation of IQM-95,333, a highly selective CCKA receptor antagonist with anxiolytic-like activity in animal models". British Journal of Pharmacology . 121 (4): 759–67. doi:10.1038/sj.bjp.0701186. PMC   1564744 . PMID   9208145.
  6. ↑ Blandizzi, C; Lazzeri, G; Colucci, R; Carignani, D; Tognetti, M; Baschiera, F; Del Tacca, M (1999). "CCK1 and CCK2 receptors regulate gastric pepsinogen secretion". European Journal of Pharmacology. 373 (1): 71–84. doi:10.1016/S0014-2999(99)00212-5. hdl: 11577/3166290 . PMID   10408253.
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