A5064573477- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Diabetes Treatment and Management
- Cholesterol and Lipid Metabolism
- Drug Transport and Resistance Mechanisms
- Peroxisome Proliferator-Activated Receptors
- Mass Spectrometry Techniques and Applications
- Pharmacological Effects and Assays
- Adipose Tissue and Metabolism
- Neuroscience and Neuropharmacology Research
- Cannabis and Cannabinoid Research
- Machine Learning in Bioinformatics
- Protein Structure and Dynamics
- Chemical Synthesis and Analysis
- Various Chemistry Research Topics
- Pancreatic function and diabetes
- Advanced Chemical Physics Studies
- Biochemical Analysis and Sensing Techniques
- DNA and Nucleic Acid Chemistry
- Insect and Pesticide Research
- Enzyme Structure and Function
- Diet and metabolism studies
- Educator Training and Historical Pedagogy
University of Glasgow
2015-2025
Heptares Therapeutics (United Kingdom)
2021
University of Sussex
1987-2020
University of Southern Denmark
2014-2017
Heriot-Watt University
2017
Institute of Molecular and Cell Biology
2017
Medical Research Council
2016
University of Leicester
2016
Lawrence Livermore National Laboratory
2013
Novartis (United Kingdom)
2013
Bringing new medicines to the market depends on rapid discovery of and effective drugs, often initiated through biological testing many thousands compounds in high-throughput screening (HTS). Mixing together into pools for is one way accelerate this process reduce costs. This paper contains both theoretical experimental data which suggest that careful selection be pooled necessary order risk reactivity between within pools.
TUG-891 [3-(4-((4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein–coupled 120, or GPR120). Herein, we have used to further define function of FFA4 this compound in proof principle studies indicate therapeutic potential receptor. displayed similar signaling properties LCFA <i>α</i>-linolenic at human across various assay end points,...
GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects therefore emerging as new potential target for treatment type 2 diabetes metabolic diseases. Further investigation however hindered by the lack suitable modulators. Screening FFA1 ligands provided lead with moderate activity on selectivity over FFA1. Optimization led discovery first potent selective agonist.
Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane for short-chain acids (SCFAs) that implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency FFA2 can hence be considered as highly potent given its size. Propionate, however, does not discriminate between the closely related FFA3 (GPR41). To identify FFA2-selective ligands understand molecular basis selectivity, targeted library of small carboxylic was...
FFA2 is a G protein-coupled receptor that responds to short chain fatty acids and has generated interest as therapeutic target for metabolic inflammatory conditions. However, definition of its functions been slowed by dearth selective ligands can distinguish it from the closely related FFA3. At present, only described suffer poor potency, altered signaling due allosteric modes action, or lack function at non-human orthologs receptor. To address need novel ligands, we synthesized two...
Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action mostly unclear. Fatty acids may contribute by acting precursors signalling molecules or direct activity on receptors. The medium- long-chain NEFA receptor FFA1 (free fatty acid 1, previously known GPR40) has been linked to enhancement glucose-stimulated secretion, whereas FFA4 4, GPR120) insulin-sensitising anti-inflammatory effects, both...
The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that assumed to mimic endogenous long-chain agonists. Here, we report preliminary structure-activity relationship studies a previously disclosed nonacidic sulfonamide agonist. Mutagenesis indicate compounds orthosteric agonists despite absence carboxylate function. preferred showed full agonist activity on...
The capa peptide receptor, capaR (CG14575), is a G-protein coupled receptor (GPCR) for the D. melanogaster neuropeptides, Drm-capa-1 and -2 (capa-1 -2). To date, family constitutes only known nitridergic peptides in insects, so mechanisms physiological function of ligand-receptor signalling this are interest. Capa induces calcium signaling via with EC50 values capa-1 = 3.06 nM capa-2 4.32 nM. undergoes rapid desensitization, internalization b-arrestin-2 mediated mechanism but rapidly...
The poorly characterized G-protein-coupled receptor GPR35 has been suggested as a potential exploratory target for the treatment of both metabolic disorders and hypertension. It also indicated to play an important role in immune modulation. A major impediment validation these concepts further study this paucity pharmacological tools that interact with GPR35. Using receptor-β-arrestin-2 interaction assay human rat orthologues GPR35, we identified number compounds possessing agonist activity....
When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered activated solely by synthetic (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether RASSL free fatty acid 2 (FFA2) could be developed on basis pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology...
Volatile small molecules, including the short-chain fatty acids (SCFAs), acetate and propionate, released by gut microbiota from catabolism of nondigestible starches, can act in a hormone-like fashion via specific G-protein-coupled receptors (GPCRs). The primary GPCR targets for these SCFAs are FFA2 FFA3. Using transgenic mice which was replaced an altered form called Designer Receptor Exclusively Activated Drugs (FFA2-DREADD), but FFA3 is unaltered, newly identified FFA2-DREADD agonist...
Abstract Two algorithms for the selection of subsets compounds from chemical databases are presented and discussed. The first is designed to select representative whilst second intended which cover available property space. Both make use calculated physicochemical parameters in contrast more common methods based on molecular fingerprints. This an approach similarity has proved successful past. illustrated with examples
Background and purpose: The CB 1 cannabinoid receptor the β 2 ‐adrenoceptor are G protein‐coupled receptors (GPCRs) co‐expressed in many tissues. present study examined physical functional interactions between these a heterologous expression system primary human ocular cells. Experimental approach: Physical ‐adrenoceptors were assessed using bioluminescence resonance energy transfer (BRET). Functional evaluated by examining trafficking, as well extracellular signal‐regulated kinase (ERK)...
Allosteric agonists are powerful tools for exploring the pharmacology of closely related G protein-coupled receptors that have nonselective endogenous ligands, such as short chain fatty acids at free acid 2 and 3 (FFA2/GPR43 FFA3/GPR41, respectively). We explored molecular mechanisms mediating activity 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide (4-CMTB), a recently described phenylacetamide allosteric agonist modulator ligand function human FFA2, by combining our previous...
Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report discovery highly potent FFA1 agonist with favorable physicochemical pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days chronic dosing.
The long-chain fatty acid receptor FFA4 (previously GPR120) is receiving substantial interest as a novel target for the treatment of metabolic and inflammatory disease. This study examines first time detailed mode binding both synthetic agonist ligands at by integrating molecular modeling, mutagenesis, ligand structure-activity relationship approaches in an iterative format. In doing so, residues required agonists to have been identified. has allowed refinement well validated model...
Analysis of the roles short chain fatty acid receptor, free 3 receptor (FFA3), has been severely limited by low potency its endogenous ligands, crossover function these on closely related 2 and a dearth FFA3-selective synthetic ligands. From series hexahydroquinolone-3-carboxamides, we demonstrate that 4-(furan-2-yl)-2-methyl-5-oxo-<i>N</i>-(<i>o</i>-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide is selective moderately potent positive allosteric modular (PAM)-agonist FFA3 receptor....