1,4-Benzodiazepine Peripheral Cholecystokinin (CCK-A) Receptor Agonists

Sherrill, Ronald G.; Berman, Judd; Birkemo, Lawrence; Croom, Dallas K.; Dezube, Milana; Ervin, Gregory N.; Grizzle, Mary K.; James, M K; Johnson, Michael F.; Queen, Kennedy L.; Rimele, Thomas J.; Vanmiddlesworth, Frank; Sugg, Elizabeth E.

doi:10.1016/s0960-894x(01)00164-0

Cited by 30 publications

(17 citation statements)

References 13 publications

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“…The ability of CCK to stimulate satiety has been responsible for efforts to target this receptor as a potential treatment for obesity. Indeed, agonists of the type 1 CCK receptor (CCK1R) have been developed (5)(6)(7)(8) and studied in clinical trials for obesity (8,9). Although these agents did stimulate weight loss, this was not quantitatively greater than acute dieting alone.…”

mentioning

confidence: 99%

A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

Desai

Harikumar

Miller

2014

Journal of Biological Chemistry

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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.

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mentioning

confidence: 99%

A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

Desai

Harikumar

Miller

2014

Journal of Biological Chemistry

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“…10,15,16 Indeed, multiple companies were successful in developing small-molecule CCK agonists, with some of these agents entering into clinical trials. [17][18][19][20] Whereas those candidates that had been shown to be quite active in vitro in cell studies and in vivo in animal studies were also shown to reduce food intake in human clinical trials, these drugs were no better than acute dieting, the requirement that the Food and Drug Administration had in place for the approval of a diet drug. None of these agents advanced to being approved for clinical use.…”

Section: Cholecystokinin Physiologymentioning

confidence: 99%

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

et al. 2016

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The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety. There has been interest in targeting the type 1 CCK receptor (CCK1R) for drug development to provide non-caloric satiation as an aid to dieting and weight loss; however, there have been concerns about CCK1R agonists related to side effects and potential trophic impact on the pancreas. A positive allosteric modulator (PAM) of CCK action at this receptor without intrinsic agonist activity could provide a safer and more effective approach to long-term administration. In addition, CCK1R stimulus-activity coupling has been shown to be negatively affected by excess membrane cholesterol, a condition described in the metabolic syndrome, thereby potentially interfering with an important servomechanism regulating appetite. A PAM targeting this receptor could also potentially correct the negative impact of cholesterol on CCK1R function. We will review the molecular basis for binding natural peptide agonist, binding and action of small molecules within the allosteric pocket, and the impact of cholesterol. Novel strategies for taking advantage of this receptor for the prevention and management of obesity will be reviewed.International Journal of Obesity Supplements (2016) 6, S22-S27; doi:10.1038/ijosup.2016.5 INTRODUCTIONThe prevalence of obesity has been progressively increasing throughout the United States and around the world, contributing to a parallel increase in the prevalence of type 2 diabetes mellitus and its associated comorbidities. 1 These problems have been responsible for extraordinary morbidity, suffering, loss in productivity and premature mortality. In spite of major efforts to develop effective weight reduction diets, diet aids, medications, medical devices and surgical procedures, the trajectory for this continues in the wrong direction. Bariatric surgery has proven to be quite effective in patients with morbid obesity; 2 however, this is quite expensive and not scalable, certainly not keeping up with the increasing prevalence of the most severe end of this clinical continuum. The activity of acute dieting and exercise has been similarly effective in inducing weight loss; however, it has not been durable, with an extremely high incidence of regaining weight to or even beyond the starting point. After a long hiatus in approved drugs, three new diet medications have recently been approved, 3-5 but all carry concerns about safety, and there are requirements for registration and careful clinical follow-up, re...

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“…We have developed an efficient solid-phase synthesis for 2,5-dihydrobenzo[f ] [1,2,5]thiadiazepine-1,1-dioxides using three types of commercially available building blocks: Fmocprotected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromoketones. Cyclic products 7, except for the CF 3 derivatives, were obtained with good crude purities (53−77%), and their structures were confirmed by 1D and 2D NMR spectra.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…1−3 In addition, some of them exhibit antitumor or cholecystokinin (CCK-A) agonistic activity. 4,5 In recent years, attention has also been focused on the preparation and biological screening of the structurally isomeric 3H-benzo[e] [1,4]diazepines II. However, the analogous derivatives III and IV have seldom been studied, and only a few reports have described their synthesis or properties.…”

Section: ■ Introductionmentioning

confidence: 99%

Solid-Phase Synthesis of Trisubstituted 2,5-Dihydrobenzo[f][1,2,5]thiadiazepine 1,1-Dioxide Derivatives

Fülöpová

Krchňák

2014

ACS Comb. Sci.

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The solid-phase synthesis of trisubstituted 2,5-dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides is reported. Acyclic polymer-supported intermediates were prepared using commercially available building blocks: Fmoc-protected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromoketones. The acyclic precursors underwent acid-mediated release from the resin and the cyclization was completed in solution.

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1,4-Benzodiazepine Peripheral Cholecystokinin (CCK-A) Receptor Agonists

Cited by 30 publications

References 13 publications

A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

Solid-Phase Synthesis of Trisubstituted 2,5-Dihydrobenzo[f][1,2,5]thiadiazepine 1,1-Dioxide Derivatives

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