Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cholecystokinin receptor type 1 (CCK1R) is a G protein-coupled receptor (GPCR) that is involved in several biological processes including the regulation of the secretion of digestive enzymes. The peptide hormone cholecystokinin (CCK) binds to CCK1R, which is an important pharmacological target for several diseases, including obesity. Interestingly, nutritional dietary peptides also appear to activate CCK1R, and may play a role in CCK1R signaling in the gut. In this study, a novel technique to screen for CCK1R ligands based on affinity-selection is described. Functional expressed CCK1R is reconstituted into membrane nanoparticles called NABBs (nanoscale apo-lipoprotein bound bilayers). NABBs are native-like bilayer membrane systems for incorporation of GPCRs. CCK1R-NABBs were characterized using a fluorescently labeled CCK analog and can be used as a cutting-edge technology to screen for CCK1R ligands using affinity-selection mass spectrometry.
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PMID:Development of a CCK1R-membrane nanoparticle as a fish-out tool for bioactive peptides. 2545 29

Cholecystokinin (CCK) acts at the type 1 cholecystokinin receptor (CCK1R) to elicit satiety and is a well-established drug target for obesity. To date, small molecule agonists have been developed, but have failed to demonstrate adequate efficacy in clinical trials, and concerns about side effects and potential toxicity have limited further development of full agonists. The use of positive allosteric modulators (PAMs) without intrinsic agonist activity that are active only for a brief period of time after a meal might represent a safer alternative. Here, we propose a possible novel strategy to develop such compounds by modifying the agonist 'trigger' of an existing small molecule agonist. We have studied analogues of the 1,5-benzodiazepine agonist, GI181771X, in which the N1-isopropyl agonist 'trigger' was modified. While agonist activity was greatly reduced in these compounds, they acted as negative, rather than positive modulators. The parent drug was also found to exhibit no positive modulation of CCK action. Receptor structure-activity relationship studies demonstrated that the mode of docking these derivatives was distinct from that of the parent compound, perhaps explaining their action as negative allosteric modulators. We conclude that this outcome is likely characteristic of the parental agonist, and that this strategy may be more successfully utilized with a parental ago-PAM, possessing intrinsic positive modulatory activity.
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PMID:Elimination of a cholecystokinin receptor agonist 'trigger' in an effort to develop positive allosteric modulators without intrinsic agonist activity. 2586 98

The type 1 cholecystokinin receptor (CCK1R) has multiple physiologic roles relating to nutrient homeostasis, including mediation of postcibal satiety. This effect has been central in efforts to develop agonists of this receptor as part of a program to manage and/or prevent obesity. While a number of small molecule CCK1R agonists have been developed, none have yet been approved for clinical use, based on inadequate efficacy, side effects, or the potential for toxicity. Understanding the molecular details of docking and mechanism of action of these ligands can be helpful in the rational refinement and enhancement of small molecule drug candidates. In the current work, we have defined the mechanism of binding and activity of two triazolobenzodiazepinones, CE-326597 and PF-04756956, which are reported to be full agonist ligands. To achieve this, we utilized receptor binding with a series of allosteric and orthosteric radioligands at structurally related CCK1R and CCK2R, as well as chimeric CCK1R/CCK2R constructs exchanging residues in the allosteric pocket, and assessment of biological activity. These triazolobenzodiazepinones docked within the intramembranous small molecule allosteric ligand pocket, with higher affinity binding to CCK2R than CCK1R, yet with biological activity exclusive to or greatly enhanced at CCK1R. These ligands exhibited cooperativity with benzodiazepine binding across the CCK1R homodimeric complex, resulting in their ability to inhibit only a fraction of the saturable binding of a benzodiazepine radioligand, unlike other small molecule antagonists and agonists of this receptor. This may contribute to the understanding of the unique short duration and reversible gallbladder contraction observed in vivo upon administration of these drugs.
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PMID:Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex. 2665 2

Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety. In functional in vitro assays C2816 retained full agonism at GLP-1R and CCKR1 at lower potency compared to parent molecules, whereas a previously reported fusion peptide in the opposite orientation, (pGlu-Gln)-CCK-8/exendin-4, exhibited no activity at either receptor. Acutely, in vivo, C2816 increased cFos in key central nuclei relevant to feeding behavior, and reduced food intake in wildtype (WT), but less so in GLP-1R-deficient (GLP-1RKO), mice. In sub-chronic studies in diet-induced obese (DIO) mice, C2816 exerted superior reduction in body weight compared to co-administration of AC3174 and AC170222 albeit at a higher molar dose. These data suggest that the synergistic pharmacological effects of GLP-1 and CCK pathways can be harnessed in a single therapeutic peptide.
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PMID:A GLP-1:CCK fusion peptide harnesses the synergistic effects on metabolism of CCK-1 and GLP-1 receptor agonism in mice. 2978 92

Allosteric modulation of receptors provides mechanistic safety while effectively achieving biologic endpoints otherwise difficult or impossible to obtain by other means. The theoretical case has been made for the development of a positive allosteric modulator (PAM) of the type 1 cholecystokinin receptor (CCK1R) having minimal intrinsic agonist activity to enhance meal-induced satiety for the treatment of obesity, while reducing the risk of side effects and/or toxicity. Unfortunately, such a drug does not currently exist. In this work, we have identified a PAM agonist of the CCK1R, SR146131, and determined its putative binding mode and receptor activation mechanism by combining molecular modeling, chimeric CCK1R/CCK2R constructs, and site-directed mutagenesis. We probed the structure-activity relationship of analogs of SR146131 for impact on agonism versus cooperativity of the analogs. This identified structural features that might be responsible for binding affinity and potency while retaining PAM activity. SR146131 and several of its analogs were docked into the receptor structure, which had the natural endogenous peptide agonist, cholecystokinin, already in the bound state (by docking), providing a refined structural model of the intact CCK1R holoreceptor. Both SR146131 and its analogs exhibited unique probe-dependent cooperativity with orthosteric peptide agonists and were simultaneously accommodated in this model, consistent with the derived structure-activity relationships. This provides improved understanding of the molecular basis for CCK1R-directed drug development.
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PMID:Molecular Basis of Action of a Small-Molecule Positive Allosteric Modulator Agonist at the Type 1 Cholecystokinin Holoreceptor. 3059 38

Hepatocellular carcinoma (HCC) is the fastest growing cancer worldwide in part due to the obesity epidemic and fatty liver disease, particularly nonalcoholic steatohepatitis (NASH). Chronic inflammation with the release of cytokines and chemokines with activation of hepatic stellate cells results in changes of the liver extracellular matrix (ECM) that predisposes to the development of HCC. Blood levels of the gastrointestinal peptide cholecystokinin (CCK) are increased in humans and mice consuming a high-fat diet. We found that the CCK-B receptor (CCK-BR) expression increased in the livers of mice with NASH. Treatment of mice with a CCK-BR antagonist, proglumide, prevented NASH, lowered hepatic inflammatory cytokines and chemokines, reduced oxidative stress, decreased F4/80+ hepatic macrophages, and prevented HCC. CCK-AR and CCK-BR expression was increased in both murine and human HCC cell lines compared to that of normal liver, and CCK stimulated the growth of wild-type and CCK-A receptor knockout HCC cells in vitro, but not CCK-BR knockout cells suggesting that the CCK-BR mediates proliferation. Proglumide therapy significantly reduced growth by 70% and 73% in mice bearing Dt81Hepa1-6 or in RIL-75 HCC tumors, respectively. Immunohistochemistry of a human liver tissue microarray with a selective CCK-BR antibody revealed staining of human HCC and no staining in normal liver.
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PMID:Targeting the Cholecystokinin Receptor: A Novel Approach for Treatment and Prevention of Hepatocellular Cancer. 3311 80


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