A5000212836- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Pharmacological Receptor Mechanisms and Effects
- Diabetes Treatment and Management
- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Cancer, Stress, Anesthesia, and Immune Response
- RNA modifications and cancer
- Circadian rhythm and melatonin
- Chromatography in Natural Products
- Estrogen and related hormone effects
- Cell Adhesion Molecules Research
- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Chemical synthesis and alkaloids
- Adenosine and Purinergic Signaling
- Chemokine receptors and signaling
- Pharmacogenetics and Drug Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Lipid Membrane Structure and Behavior
Discovery Institute
2020-2024
Sanford Burnham Prebys Medical Discovery Institute
2020-2024
Friedrich-Alexander-Universität Erlangen-Nürnberg
2016-2020
By means of a formal structural hybridization the antipsychotic drug aripiprazole and heterocyclic catecholamine surrogates present in β2-adrenoceptor agonists procaterol BI-167107 (4), we designed synthesized collection novel hydroxy-substituted heteroarylpiperazines heteroarylhomopiperazines with high dopamine D2 receptor (D2R) affinity. In contrast to weak agonistic behavior aripiprazole, these ligands are capable effectively mimicking those interactions D2R that crucial for an active...
Abstract Fractalkine (FKN) is a membrane‐bound chemokine that can be cleaved by proteases such as ADAM 10, 17, and cathepsin S to generate soluble fragments. Studies using different forms of the FKN yield conflicting results in vivo. These observations prompted us investigate function pharmacology two commonly used isoforms FKN, human full‐length (sFKN), domain only (cdFKN). Both are prevalent literature often assumed functionally equivalent. We observed recombinant sFKN cdFKN exhibit...
Obesity has become a prevailing health burden globally and particularly in the US. It is associated with many problems, including cardiovascular disease, diabetes poorer mental health. Hence, there high demand to find safe effective therapeutics for sustainable weight loss. Cholecystokinin (CCK) been implicated as one of first gastrointestinal hormones reduce overeating suppress appetite by activating type 1 cholecystokinin receptor (CCK1R). Several drug development campaigns have focused on...
The secretin receptor (SCTR), a prototypical class B G protein-coupled (GPCR), exerts its effects mainly by activating Gαs proteins upon binding of endogenous peptide ligand secretin. SCTRs can be found in variety tissues and organs across species, including the pancreas, stomach, liver, heart, lung, colon, kidney, brain. Beyond that, modulation SCTR-mediated signaling has therapeutic potential for treatment multiple diseases, such as heart failure, obesity, diabetes. However, no ligands...
Drugs useful in prevention/treatment of obesity could improve health. Cholecystokinin (CCK) is a key regulator appetite, working through the type 1 CCK receptor (CCK1R); however, full agonists have not stimulated more weight loss than dieting. We proposed an alternate strategy to target this receptor, while reducing likelihood side effects and/or toxicity. Positive allosteric modulators (PAMs) with minimal intrinsic agonist activity would enhance action, maintaining spatial and temporal...
As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) help prevent and/or treat obesity, we recently performed high throughput screening small molecules seeking candidates that enhanced action natural agonist, CCK, thus acting as positive allosteric modulators without exhibiting intrinsic agonist action. Such probes would be expected act in temporally finite way enhance CCK induce satiety during and after meal potentially even modulate activity...
Agonists of the secretin receptor have potential applications for diseases cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists this been developed. In current work, we identified a new small molecule lead compound with pharmacological profile. We prepared characterized systematic structure-activity series around thiadiazole scaffold to better understand molecular determinants its activity. were able enhance in vitro activity maintain...
The Secretin receptor (SCTR) has been cloned as the first member of class B G protein‐coupled receptors (GPCRs) , giving rise to this highly important group therapeutic targets, which are crucial for hormonal homeostasis . Despite wide recognition their functional importance, development potent small molecule ligands Class GPCRs remained challenging To date, no other than secretin peptide and its close analogs known interact with SCTRs, despite relevance in multiple diseases, such heart...
Class B G protein-coupled receptors (GPCRs) are a highly important group of therapeutic targets with strong physiologic implications in cardiovascular, metabolic, or gastrointestinal systems. Endogenously activated by moderate-length peptide hormones, class GPCRs entertain complex binding mechanism to induce stimulatory signaling processes. The secretin receptor (SCTR) is prototypical member this family, having clinical relevance multiple diseases including heart failure, digestive...