Cholecystokinin regulates appetite and reduces food intake by activating the type 1 CCK receptor (CCK1R). Attempts to develop CCK1R agonists for obesity have yielded active agents that have not reached clinical practice. In this review we discuss why, along with new strategies to target CCK1R more effectively. We examine signaling events and the possibility of developing agents that exhibit ligand-directed bias, to dissociate satiety activity from undesirable side effects. Potential allosteric sites of modulation are also reviewed, along with desired properties of a positive allosteric modulator without intrinsic agonist action as another strategy to treat obesity. These new types of CCK1R-active drugs could be useful as stand-alone agents or as part of a rational drug combination for management of obesity.

Background: Type 1 CCK receptor function is affected by a high cholesterol environment. Results: The CCK1R Y140A mutant has ligand binding and activation characteristics similar to wild type CCK1R in high cholesterol. Conclusion: This mutant mimics CCK1R structure in high cholesterol. Significance: This mutant represents a powerful and unique tool for identification of ligands to correct the abnormal conformation of CCK1R in high cholesterol.

This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Cholesterol represents a structurally and functionally important component of the eukaryotic cell membrane, where it increases lipid order, affects permeability, and influences the lateral mobility and conformation of membrane proteins. Several G protein-coupled receptors have been shown to be affected by the cholesterol content of the membrane, with functional impact on their ligand binding and signal transduction characteristics. The effects of cholesterol can be mediated directly by specific molecular interactions with the receptor and/or indirectly by altering the physical properties of the membrane. This review focuses on the importance and differential effects of membrane cholesterol on the activity of cholecystokinin (CCK) receptors. The type 1 CCK receptor is quite sensitive to its cholesterol environment, while the type 2 CCK receptor is not. The possible structural basis for this differential impact is explored and the implications of pathological states, such as metabolic syndrome, in which membrane cholesterol may be increased and CCK1R function may be abnormal are discussed. This is believed to have substantial potential importance for the development of drugs targeting the CCK receptor.

Cholecystokinin (CCK) is an important satiety factor, acting at type 1 receptors (CCK1Rs) on vagal afferent neurons; however, CCK agonists have failed clinical trials for obesity. We postulated that CCK1R function might be defective in such patients due to abnormal membrane composition, such as that observed in cholesterol gallstone disease. Due to the challenges in directly studying CCK1Rs relevant to appetite control, our goal was to develop and apply a method to determine the impact of a patient's own cellular environment on CCK stimulus-activity coupling and to determine whether CCK sensitivity correlated with the metabolic phenotype of a high-risk population. Wild-type CCK1Rs were expressed on leukocytes from 112 Hispanic patients by using adenoviral transduction and 24-h culture, with quantitation of cholesterol composition and intracellular calcium responses to CCK. Results were correlated with clinical, biochemical, and morphometric characteristics. Broad ranges of cellular cholesterol and CCK responsiveness were observed, with elevated cholesterol correlated with reduced CCK sensitivity. This was prominent with increasing degrees of obesity and the presence of diabetes, particularly when poorly controlled. No single standard clinical metric correlated directly with CCK responsiveness. Reduced CCK sensitivity best correlated with elevated serum triglycerides in normal-weight participants and with low HDL concentrations and elevated glycated hemoglobin in obese and diabetic patients. CCK responsiveness varies widely across the population, with reduced signaling in patients with obesity and diabetes. This could explain the failure of CCK agonists in previous clinical trials and supports the rationale to develop corrective modulators to reverse this defective servomechanism for appetite control. This trial was registered at www.clinicaltrials.gov as NCT03121755.