CCK-B receptors

This peptide itself has no selectivity for the two CCK receptors, CCK-A and B, which have so far been established to stimulate IP3/DAG while, like substance P, can close potassium channels to increase neuronal activity. The CCK-B receptor is thought to predominate in the CNS but species differences may make this interpretation difficult. It has a wide distribution in the CNS but is also found in the gut whereas the CCK-A receptor is more restricted but is found in the hypothalamus, hippocampus and in the brainstem. There are high levels of the natural peptide, CCK-8 in cortex, hippocampus, hypothalamus, ventral tegmentum, substantia nigra, brainstem and spinal cord. CCK is one of the most abundant peptides in the brain and CCK co-exists with dopamine, substance P, 5-HT and vasopressin. Interestingly, in the dopamine areas, CCK co-exists in the mesolimbic pathways but in the nigrostriatal projections, the peptide and... 

Finally, the peptide can induce anxiety and panic in normal and anxious volunteers. Some synthetic CCK-B receptor antagonists are chemically similar to the benzodiazepine anxiolytics. Again, the clinical role of CCK manipulation in anxiety remains to be resolved. 

CCK-B. Protease inhibitors that slow the degradation and inactivation of endogenous CCK promote satiety via CCK-A receptor. By contrast, the CCK-B receptor is important in mediating anxiety and panic attacks, and CCK antagonists are in clinical use to treat these symptoms. 

CCK8 concentrations were found to be lower in panic patients than in normal control subjects (Brambilla et al. 1993) and the CCK-B receptors were hyper-sensitive in panic disorders (Akiyoshi et al. 1996). Accordingly, CCK-B receptor agonists such as pentagastrin or CCK-4 have panic-like anxiogenic effects in humans (Radu et al. 2002). Clinical trials, however, have provided inconclusive data about the anxiolytic potential of CCK-B antagonists (Shlik et al. 1997). 

A gastrinlike neuropeptide, CCK exists in the central nervous system both as an octapeptide [CCK-8] and as a tetrapeptide (CCK-4) (Rex et al. 1994b). The octapeptide CCK-8 occurs predominantly in sulfated form and is one of the most abundant neuropeptides in the central nervous system (Rex et al. 1994b]. Two major subtypes of CCK receptors, labeled as CCK-A and CCK-B receptors, have been identified (Hill et al. 1993]. At this point, the most promising neuropeptide receptor to target for the treatment of anxiety may be the CCK-B receptor. This receptor is widely distributed throughout... 

Evidence of the involvement of CCK-B receptors in the neurobiology of anxiety has been strengthened by the findings that a closely related peptide, pentagastrin, produces dose-related and time-limited symptoms of social anxiety in both control subjects and patients with social phobia undergoing experimental social interactions (Uhde et al. 1993). Pentagastrin is a pentapeptide whose final tetrapeptide is identical to CCK-4. 

Bradwejn J, Koszycki D, Payeur R Study of the replication of action of cholecystokinin in panic disorders. Am J Psychiatry 149 962-964, 1992c Bradwejn J, Koszycki D, Couetoux-Dutertre AC, et al L-365,260, a CCK-B receptor antagonist, blocks CCK-4 panic (oral presentation). Presented at the annual meeting of the Anxiety Disorders Association of America (NR 235), Charleston, SC, March 20, 1993... 

Derrien M, McCort-Tranchepain 1, Ducos B, et al Eleterogeneity of CCK-B receptors involved in animal models of anxiety. Pharmacol Biochem Behav 49 133, 1994... 

Yuki H, Nishida A, Miyake A et al. (1997) YM022, a potent and selec-tive gastrin/CCK-B receptor antagonist, inhibits peptone meal-induced gastric secretion in Heidenhain pouch dogs. Dig Dis Sci 42 707-714... 

The gastrin receptor is one of the receptors that bind cholecystokinin (Table 13.4), and is known as the CCK-B receptor it is another member of the G-protein-coupled receptor family. 

CCK) CCK-B receptor amide with a Tyr sulfonic acid system solid-phase V"-Boc chemistry... 

Gastrin CCK-B receptor 14- and 17-residue peptide amide with a Glu rich region Stimulate gastric acid secretion Solution-phase and solid-phase V -Fmoc chemistry... 

Modification of the 3-amide to give a urea linkage as in (27) led to a reduction in CCK-A receptor affinity. Importantly, discrimination between CCK-A and CCK-B receptors by (27)... 

Cholecystokinin. Cholecystokinin (CCK) is one of the most abundant neurotransmitters in the central nervous system. Two CCK receptor subtypes have been cloned to date, that is, CCK-A (Alimentary), which are primarily located in the periphery, and CCK-B (Brain) (219). CCK-B receptors are widely distributed throughout the brain, but have particularly high densities in the hypothalamus, limbic system, basal ganglia, hippocampus, and brain stem (219). CCK-4 (a tetrapeptide) and CCK-8S (a sulfated oc-... 

The discovery of the first nonpetide CCK antagonist, the natural product asperlicin, in 1985 (495) shifted the medicinal chemistry focus from peptides to small molecule antagonists (496,497).CCK-B receptors are the dominant isoform in the brain, and antagonists at this subtype are potential anxiolytics. Many CCK-B antagonists also modulate gastric acid secretion through peripheral CCK-B (gastrin) receptors. 

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