Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity. 1. Optimization of the Agonist “Trigger”

Aquino, Christopher; Armour, Duncan; Berman, Judd; Birkemo, Larry S.; Carr, Robin A. E.; Croom, Dallas K.; Dezube, Milana; Dougherty, R. W.; Ervin, Gregory N.; Grizzle, Mary K.; Head, J. E.; Hirst, Gavin C.; James, M K; Johnson, Michael F.; Miller, Laurence J.; Queen, Kennedy L.; Rimele, Thomas J.; Smith, David Norman; Sugg, Elizabeth E.

doi:10.1021/jm950626d

Cited by 93 publications

(88 citation statements)

References 27 publications

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“…A key molecule used in these studies was the 1,5-benzodiazepine developed at GlaxoSmithKline Research Laboratories, GI181771X, which has a unique functional profile, being a type 1 CCK receptor agonist and a type 2 CCK receptor antagonist (4,5). This provided an ideal ligand to study binding and activation mechanisms of the two closely related CCK receptors.…”

mentioning

confidence: 99%

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Harikumar

Cawston

Lam

et al. 2013

Journal of Biological Chemistry

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Background: Cholecystokinin receptor type 1 (CCK1R) stimulates satiety. Results: Binding and activity of a CCK1R agonist/CCK2R antagonist are studied at wild-type and chimeric receptors, and ligand-guided model refinement is utilized. Conclusion:The small molecule agonist docking site is distinct from the antagonist site, with benzodiazepines docked with consistent pose, including approximation with Leu 7.39 . Significance: The molecular model and determinants for small molecule agonist action should facilitate drug development.

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mentioning

confidence: 99%

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Harikumar

Cawston

Lam

et al. 2013

Journal of Biological Chemistry

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“…In recent years, smallmolecule agonists have been described, even for receptors for larger hormones like insulin, TPO, and EPO (18)(19)(20), but none of these receptors belong to the GPCR superfamily. Within the GPCRs, small-molecule agonists have been described, e.g., for the arginine vasopressin V-2 receptor, the somatostatin receptor, the bradykinin receptor, the cholecystokinin receptor, the angiotensin II receptor, and the growth hormone secretagogue receptor (21)(22)(23)(24)(25)(26). However, none of these GPCRs belong to the B family, and the natural ligands are all either fairly small or have a defined secondary structure.…”

mentioning

confidence: 99%

Small-molecule agonists for the glucagon-like peptide 1 receptor

Knudsen¹,

Kiel

Teng

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

198

205

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The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.ago-allosteric modulator ͉ allosteric ͉ G protein-coupled receptor ͉ screening ͉ cAMP

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“…43 It also provided molecular insights into the determinants of biological activity, with evidence for a key interaction between a 'trigger functionality' within a benzodiazepine agonist and the receptor residues it likely interacts with. 20 Once again, this model had great predictive power, being able to effectively distinguish CCK1R agonists from CCK1R antagonists. 43 This has provided clear evidence of the differences in the shape of this pocket when in inactive and active conformations.…”

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 92%

“…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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Discovery of 1,5-Benzodiazepines with Peripheral Cholecystokinin (CCK-A) Receptor Agonist Activity. 1. Optimization of the Agonist “Trigger”

Cited by 93 publications

References 27 publications

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Small-molecule agonists for the glucagon-like peptide 1 receptor

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

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