Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK1 and CCK2. Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK1 and CCK2 antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK1 and CCK2 antagonist. CCK1 antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK2 antagonists might have application for the treatment of gastric acid secretion and anxiety disorders. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 5, 559–605, 2003

Cholecystokinin antagonists: Pharmacological and therapeutic potential

2.04 – Pyrroles and their Benzo Derivatives: Applications

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.

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Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.

Both mu-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing mu-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16-22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2 receptors in vivo.

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Induced association of mu opioid (MOP) and type 2 cholecystokinin (CCK2) receptors by novel bivalent ligands

Recognition that the gastrointestinal polypeptide hormone gastrin affects diverse actions, such as gastric acid secretion and gastrointestinal cell growth in peripheral tissues, has prompted efforts to obtain agents that inhibit its action. This has mainly been approached through the use of CCK2 receptor antagonists which also have the potential to inhibit cholecystokinin-mediated CNS effects, such as anxiety and pain. However, results obtained so far from compounds of this type in the clinic have been disappointing due to their low oral bioavailability. This has resulted from physicochemical limitations of the compounds examined, such as solubility, and attempts to further optimise these initial candidates have also spawned CCK2 receptor antagonists based on other structural types. These new compounds may ultimately demonstrate therapeutic utility for CCK2 receptor antagonists.

Stephen B. Freedman

Papers

Benzolactams as non-peptide cholecystokinin receptor ligands

Development of 1,4-Benzodiazepine Cholecystokinin Type B Antagonists.

Multipurpose receptor ligands: β-carboline cholecystokinin antagonists