Cholecystokinin antagonist

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 CCK_A and CCK_B (also called CCK-1 and CCK-2). CCK_A 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). CCK_B 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 antagonist is the non-selective antagonist proglumide, which blocks both CCK_A and CCK_B, and was originally developed for the treatment of stomach ulcers. This action derived from its blockade of CCK_A 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 CCK_B receptors in the brain.

Newer drugs have since been developed which are selective for one or other of the CCK receptors. Selective CCK_A 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 antagonist research has focused on the development of selective CCK_B 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 CCK_B 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 CCK_B antagonists such as L-365,260, L-369,293, YF-476, RP-69758, LY-288,513, PD-145,942 and the CCK_B 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]

CCK_A receptors are also expressed in the brain to some extent, and interestingly IQM-95333, an antagonist selective for this population of CCK_A receptors, was also found to reduce anxiety in animal models.^[5] Conversely, inhibition of CCK_B receptors in the gut produces similar inhibition of secretion of gastric acid and pepsinogen enzymes as is seen with inhibition of CCK_A receptors,^[6] suggesting that while the CCK_A and CCK_B 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.

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. 
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. 
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 et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1564744. 
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. PMID 10408253.