Octapeptide CCK

CCK has been detected in two principal forms, ie, the traditional 33-amino acid peptide, and an octapeptide CCK-8. The intestine produces mainly CCK-33 (133) and the brain produces mainly CCK-8 (132). The CCK precursor contains one copy of CCK-33 (133,134) this peptide is flanked on both ends with double basic residues, whereas CCK-8 is formed from CCK-33 by cleavage of a single basic residue. 

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... 

Dodd PR, Edwardson JA, Dockray GJ The depolarization-induced release of cholecystokinin C-terminal octapeptide (CCK-8) from rat synaptosomes and brain slices. Regul Pept 1 17-19, 1980... 

Cholecystokinin receptors are the GPCRs CCK-A and CCK-B. The C-terminal sulfated octapeptide CCK fragment (CCK8) is a major neuropeptide. CCK is involved in anorexia, cardiovascular tonus, central respiratory control, nociception, pancreatic exocrine secretion, gastric emptying, memory, vigilance and emotional states such as anxiety and panic. 

Peptide Anorectics - The role of cholecystokinin-octapeptide (CCK-8) in the control of appetitive behavior has been reviewed recently and its clinical efficacy has been demonstrated in lean and obese subjects. Ceruletide, which is structurally related to CCK-8, decreases solid food intake and subjective hunger ratings in patients. A smaller fragment of cholecystokinin, CCK-4 inhibits food intake in rats at doses approximately 10-fold greater than those needed to produce the same effect with CCK-8. 

Fig. 6.1.2 Convergent enzymatic synthesis of the C-terminal cholecystokinin octapeptide (CCK-8)...

Cholecystokinin (CCK) is one of the brain-gut peptides. Its most abundant form in the brain is the C-terminal sulphated octapeptide fragment CCK8, which interacts with the same affinity with both CCK receptor subtypes, CCK-A and CCK-B. Extensive pharmacological studies have been carried out over the last few years suggesting that CCK may participate in the neuroendocrine responses to stress (Harro et al 1993 Dauge and Lena 1998). Interestingly, CCK8 and CRH are co-locahzed in neurons of the hypothalamic PVN (Mezey etal. 1985). 

Scheme 2 Sulfation of the CCK-Octapeptide with Concentrated Sulfuric Acid after Acidolytic Removal of the Acid-Labile Protecting Groups to Yield CCK-8 U ...

Quantitative sulfation is not achieved even with a larger excess of sulfating reagent (max sulfation 80%), a fact which is not understood. On the other hand, sulfation of a suitably protected CCK-8 linked to PAM resin with pyridine/S03 proceeds smoothly (Scheme 10) and upon ammonolysis, the CCK-octapeptide is isolated in 23% overall yield. 98 ... 

CCK is a peptide with 33 amino acids originally isolated from pork intestine. Its action on insulin secretion is very weak in humans. Several smaller molecular forms, however, have been isolated from gut mucosa and from brain. Both the C-terminal octapeptide (CCK8) and the tetrapeptide (CCK4) stimulate insulin release in vitro (Okabayashi et al., 1983 Herman-sen, 1984 Verspohl et al.. 1986b Zawalich et al., 1987). 

Intravenous infusion of an octapeptide derivative of CCK decreases the level of hunger and reduces food intake in normal subjects (Kissileff et al. 1981). This effect is reversed by loxiglumide, a specific CCK-A antagonist (Gutzwiller et al. 2000). 

Secretin stimulates the secretion of pancreatic juice and bicarbonate, but stumilation of the secretion of pancreatic enzymes is inconsistent. Addition of CCK (or a synthetic equivalent) to the secretin stimulation test provides a stimulus to the secretion of pancreatic enzymes, allowing a more complete assessment of pancreatic reserve than can be obtained with secretin alone. The functional activity of CCK resides in the C-terminal octapeptide sequence (CCK-8), and either this octapeptide or ceruletide (a synthetic decapeptide identical to the natural decapeptide cerulein) can be used to stimulate pancreatic enzyme secretion (Figure 48-7). 

CCK is also found in high concentrations in the brain, but mainly as the C-terminal octapeptide [2,3]. Usually native CCK-8 is sulphated on tyrosine 7 (CCK-8S, figure 1). 

C-terminal octapeptide SQ 19844 Kinevac. C H N -OjjS mol wt [143.29. C 51.48%, H 5.47%, N 12.25%, O 22.39%, S 8.41%. The C-terminal octapeptide of choleeys-tokinin-pancreozymin (see cholecystokinin). Structurally similar to caerulein, q.v., it evokes a variety of biological responses similar to CCK-PZ, includiug smooth-muscle contraction of the gall bladder and small intestine, relaxation of the choledochoduodenal junction, protein secretion by the pancreas and acid secretion by the stomach. It is more active than cholecystokinin on a weight or molar basis. Initial isoln V. Mutt, J. E. Jorpes, Eur. J. Biochem. 6, 156 (1968). Prepn M. A. Ondetti et al. Get. pat. 1,922,185 corresp to U.S. pat, 3,723,406 (1969, 1970, both to Squibb) eidem, J. Am. Chem. Soc. 92, 195 (1970), Mechanical and metabolic effects K. E. Andersson ef al., Acta Physiol... 

Cholecystoklnin (CCK) and Caerulein - The C-terminal octapeptide sequences of CCK and caerulein differ only in the presence of methionine or threonine in position 6. Since these compounds have been synthesized, a considerable number of structure-activity studies have been conducted by investigators at Squibb and at Farmitalia.° 9... 

Both the position and sulfation of the Tyr residue are critical to cholecystokinetic activities of both molecules however, the sulfated tyrosine residue i st be part of a peptide chain of certain length for optimal activity. Contrary to experience with other peptide hormones, the C-terminal octapeptide of CCK is more potent than the total molecule on a molar basis. Erspamer9 has reported preliminarily that dissociation of some of the biological activities of caerulein have been accomplished by changing its structure. New vivo and in vitro techniques for biological assay of CCK have been designed. 5573 " ... 

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