CCK-A receptor

The BZ stmcture also has provided a molecular scaffold for a number of peptide receptor ligands (26). Antagonists for the cholecystokinin (CCK-A) receptor, eg, devazepide (65), the thyrotropin-releasing hormone (TRH) receptor, eg, midazolam (66), and the /i -opiate receptor, eg, tifluadom (67), as well as a series of ras famyl transferase inhibitors, eg, BZA-2B (68) (30) have been identified (Table 4). 

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... 

JORDINSON M, DEPREZ P H, PLAYFORD R J, HEAL S, FREEMAN T 0, ALISON M, CALAM J (1996) Soybean lectin stimulates pancreatic exocrine secretion via CCK-A receptors in rats. Am J Physiol. 270 G653-9. 

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. 

Eberle-Wang K, Simansky KJ (1992) The CCK-A receptor antagonist, devazipide, blocks the anorectic action of CCK but not peripheral serotonin in rats. Pharmacol Biochem Behav 43 943-947... 

Cholecystokinin CCK-A receptor, 33-residue peptide Modulate digestion Solution-phase and... 

Based on the benzodiazepine nucleus, and an overt mimic of diazepam, one of the first successful synthetic analogs was L-364,286 (25), which had potency on CCK-A receptors similar to that of asperlicin. Better receptor affinity was achieved with 3-amide-substituted benzazepines the 2-indolyl derivative L-364,718, also known as MK-329 (26), is five orders of magnitude more potent than asperlicin (42)at CCK-A receptors and is a valuable pharmacological tool. 

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)... 

Gutzwiller, J. P., J. Drewe, S. Ketterer, R Hildebrand, A. Krautheim and C. Beglinger (2000). Interaction between CCK and a preload on reduction of food intake is mediated by CCK-A receptors in humans. Am J Physiol Regul Integr Comp Physiol 279(1) R189-95. 

The classification of CCK receptors into two sub-types is supported by the use of non-peptidic, selective competitive antagonists. L-364,718 (devazepide) was the first competitive antagonist found with high affinity for the CCK-A receptor (pKj = 9.3) [9]. This compound was developed from asperlicin (pKj = 6.2) which had been found during the screening of products of microbiological fermentation [10]. Similarly, a number of selective CCK-B receptor antagonists have been discovered such as the peptoid PD-134308 (pK = 8.5) which was derived from a chemical manipulation of CCK-4 [11]. 

Structurally, CCK-B receptors and gastrin receptors show high sequence homology ( 90%) and the human CCK-B receptor was 90% and 91% identical to those of the rat and guinea pig. CCK-A receptors cloned from the rat show only 48% homology with rat brain CCK-B receptors. The human CCK-A receptor cloned from gallbladder has >90% homology to the rat receptor [12]. 

In the mouse the CCK-A receptor and the CCK-B receptor are also found on different chromosomes, CCK-A on chromosome 5 and CCK-B on chromosome 7. 

The affinity and selectivity of 1,5-benzodiazepines with different substitution pattern was studied in either guinea-pig cortical membranes (CCK-B receptors) or in rat pancreatic membranes (CCK-A receptors) using radiolabelled binding studies. 

The CCK peptides are produced in neuroendocrine cells of the upper intestine, but also in the central nervous system where the major circulating form is represented by CCK-8. In the periphery, the action of the CCK-peptides is mediated mainly by the CCK-A receptor (37) with high affinity for the sulfated forms. Among the numerous biological effects within the gut, CCK induces... 

The biological functions of the lipo-gastrin and lipo-CCK peptides were analyzed on these two receptors of known sequence using rat pancreatic acinar cells and the tumoral rat pancreatic acinar cell line AR42J. The CCK-A receptor has been thoroughly characterized in the rat pancreatic acinar cells (140-142) and in its... 

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