Cholecystokinin antagonists: Pharmacological and therapeutic potential

Abstract

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 CCK(1) and CCK(2). 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 CCK(1) and CCK(2) 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 CCK(1) and CCK(2) antagonist. CCK(1) 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, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor

“…These new findings have generated considerable interest in the identification of antagonists of CCK2R. To date, a large panel of chemically distinct CCK2R antagonists have been discovered and used to assess the functions mediated by CCK2R in animals and humans (10). Furthermore, several of these compounds have reached clinical evaluation stages for indications such as anxiety and panic disorders, sleep disorders, drug dependence, pain, gastroesophagus reflux, and gastric secretion disorders (10).…”

“…To date, a large panel of chemically distinct CCK2R antagonists have been discovered and used to assess the functions mediated by CCK2R in animals and humans (10). Furthermore, several of these compounds have reached clinical evaluation stages for indications such as anxiety and panic disorders, sleep disorders, drug dependence, pain, gastroesophagus reflux, and gastric secretion disorders (10). However, some reference molecules believed to be pure antagonists turned out to be endowed with some agonist activity in the stomach and pancreas as well as cells expressing CCK1R or CCK2R (11)(12)(13).…”

Evidence That Interspecies Polymorphism in the Human and Rat Cholecystokinin Receptor-2 Affects Structure of the Binding Site for the Endogenous Agonist Cholecystokinin

“…In the gut, CCK2Rs regulate acid and histamine secretions, gastrointestinal motility, as well as growth in the gastric mucosa (1,2). The important physiological functions mediated by CCK receptors, and therefore their possible implication in associated disorders, have generated considerable interest in the identification of ligands that selectively activate or block CCK1R and CCK2R (6). To date, a large panel of such molecules has been designed covering a wide range of functional activities, such as full, partial, and inverse agonists, as well as antagonists (6).…”

“…The important physiological functions mediated by CCK receptors, and therefore their possible implication in associated disorders, have generated considerable interest in the identification of ligands that selectively activate or block CCK1R and CCK2R (6). To date, a large panel of such molecules has been designed covering a wide range of functional activities, such as full, partial, and inverse agonists, as well as antagonists (6). Pharmacological characterization of selective synthetic CCK2R ligands among different species pointed out an interspecies genetic polymorphism that does not alter endogenous hormone-induced signaling but markedly affects both the affinity and activity of synthetic ligands (7).…”

“…These new important data, together with our experience with the CCK1R (31), will be used to understand how some of the socalled non-peptide antagonists present partial agonist activities (7). This goal is of timely importance due to the fact that CCK2R is a biological target of therapeutic interest (6).…”