Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor

Abstract

Cholecystokinin (CCK) is a physiologically important gastrointestinal and neuronal peptide hormone, with roles in stimulating gallbladder contraction, pancreatic secretion, gastrointestinal motility and satiety. CCK exerts its effects via interactions with two structurally related class I guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), the CCK1 receptor and the CCK2 receptor. Here, we focus on the CCK1 receptor, with particular relevance to the broad spectrum of signalling initiated by activation with the natural full agonist peptide ligand, CCK. Distinct ligand-binding pockets have been defined for the natural peptide ligand and for some non-peptidyl small molecule ligands. While many CCK1 receptor ligands have been developed and have had their pharmacology well described, their clinical potential has not yet been fully explored. The case is built for the potential importance of developing more selective partial agonists and allosteric modulators of this receptor that could have important roles in the treatment of common clinical syndromes. (2010) , 90-kDa ribosomal S6 protein kinase; PI3K, class I phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; SAR, drug structure-activity relationship; Shc, Src homology/ collagen related; SOS, Drosophila homolog, Son of Sevenless British Journal of PharmacologyThe main purpose of this report is to explore the therapeutic potential of highly selective partial agonists and allosteric modulators of the type 1 cholecystokinin (CCK) receptor (CCK1 receptor). To more fully appreciate this selective role, the normal physiology and pathophysiology of this receptor and of its natural, full agonist ligand, CCK, must first be reviewed.Cholecystokinin is one of the earliest gastrointestinal hormones to be discovered, identified more than 90 years ago based on its ability to stimulate gallbladder contraction (Ivy and Oldberg, 1928). It was soon recognized to be identical to the factor responsible for stimulating pancreatic exocrine secretion (Harper and Raper, 1943). This hormone has subsequently been shown to have effects on enteric smooth muscle and on nerves at various locations in the peripheral and central nervous system (Rehfeld, 2004). One of its most important neural effects is post-cibal satiety (Kissileff et al.,

Differential Expression of Cholecystokinin A Receptor in Gallbladder Cancer in the Young and Elderly Suggests Two Subsets of the Same Disease?

“…Large body of data exists concerningseveral peptide and nonpeptidyl CCKAR modulators, and clinical potentials of these agents are under trial [37]. Our study defines two possible variants of GBC in this endemic belt.…”

Up-regulation of Cholesterol Absorption Is a Mechanism for Cholecystokinin-induced Hypercholesterolemia

“…2D shows that the CCK A71623 and pentagastrin mimicked the effect of CCK with regard to the stimulation of cholesterol absorption. Pentagastrin is ϳ968-fold selective for CCK2R over CCK1R (25), whereas A71623 is 1200-fold selective for CCK1R over CCK2R (26). The data in Fig.…”

Photodynamic Physiology—Photonanomanipulations in Cellular Physiology with Protein Photosensitizers

“…CCK-CCK receptors play important roles in both gastrointestinal (GI) and central nervous system (CNS) functions (Cawston and Miller, 2010; Yu and Smagghe, 2014), due to the wide-spread distribution of both CCK1 and CCK2 receptors (Miller and Gao, 2008; Dockray and Burdyga, 2011). Of the group A GPCR receptors, CCK1 is unique in that it can be permanently activated by photodynamic oxidation (Cui and Kanno, 1997; An et al, 2003; Cui et al, 2012).…”