The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs

G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets. Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential. One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand. As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis. Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs

4-Fluoro-N-methyl-N-(1,2,3,4-tetra­hydro­carbazol-3-yl)benzene­sulfonamide

In the title compound, C19H19FN2O2S, the hydrogenated six-membered ring of the carbazole unit adopts a half-chair conformation and the plane of the fluoro­phenyl ring forms a dihedral angle of 41.5 (1)° with respect to the carbazole mean plane. The crystal structure is segregated into layers containing the carbazole units and fluoro­phenyl rings in alternate (200) planes. The carbazole units form centrosymmetric face-to-face inter­actions [inter­planar separation = 4.06 (1) Å] and edge-to-face inter­actions in which the N—H group is directed towards an adjacent carbazole face, with a shortest H⋯C contact of 2.53 Å. The fluoro­phenyl rings form face-to-face contacts with an approximate inter­planar separation of 3.75 Å and a centroid–centroid distance of 4.73 (1) Å

The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120)

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. The current study examines for the first time the detailed mode of binding of both a long-chain fatty acid and synthetic agonist ligands at FFA4 by integrating molecular modeling, receptor mutagenesis, and ligand structure-activity relationship approaches in an iterative format. In doing so, residues required for binding of fatty acid and synthetic agonists to FFA4 have been identified. This has allowed for the refinement of a well-validated model of the mode of ligand-FFA4 interaction which will be invaluable in the identification of novel ligands and future development of this receptor as a therapeutic target. The model reliably predicted the effects of substituent variations on agonist potency, and was also able to predict the qualitative effect of binding site mutations in the majority of cases

EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of a health claim related to OptiEFAX™ and maintenance of normal blood concentrations of triglycerides pursuant to Article 13(5) of Regulation (EC) No 1924/2006

<p>Following an application from Nutrilinks Sarl, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Belgium, the Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to OptiEFAX™ and maintenance of normal blood concentrations of triglycerides. The food that is the subject of the health claim, OptiEFAX™, which is standardised pure krill oil, is sufficiently characterised in relation to the claimed effect. The claimed effect, maintenance of normal blood concentrations of triglycerides, is a beneficial physiological effect. The target population proposed by the applicant is the general population. No human studies have been provided from which conclusions could be drawn for the scientific substantiation of the claim. A cause and effect relationship has not been established between the consumption of OptiEFAX™ and maintenance of normal blood concentrations of triglycerides.</p&gt

Treatment of type 2 diabetes by free fatty acid receptor agonists

Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for Free Fatty Acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long chain FFA receptor, FFA1, improved glycaemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programmes within industry and academia aimed at improving the safety and effectiveness of these potential treatments

Marine n-3 Fatty Acids and Gene Expression in Peripheral Blood Mononuclear Cells

Intake of marine n-3 fatty acids has been shown to have beneficial effects on cardiovascular disease. Gene expression analyses in peripheral blood mononuclear cells (PBMCs) are used to understand the underlying mechanisms of action of marine n-3 fatty acids. The aim of this review was to summarize the effects mediated by marine n-3 fatty acids on gene expression in PBMCs. A systematic literature search was conducted in PubMed in May 2014 and 14 papers were included. Targeted gene expression studies were reported in 9 papers and focused on genes involved in lipid metabolism and inflammation. Whole genome transcriptome analyses were conducted in 5 papers, and processes and pathways related to atherosclerotic plaque formation such as inflammation, oxidative stress response, cell cycle, cell adhesion, and apoptosis were modulated after fish oil supplementation. PBMC gene expression profiling has a potential to clarify further the molecular effects of fish oil consumption on human health

Analysis of Spectral Irradiance Variations and Their Impact on the Performance of Different Photovoltaic Modules

I denne avhandlingen har to år med global horisontal spektral innstrålings og global vinklet spektral innstrålings data har blitt analysert for å se hvordan spektral distribusjoen varierer over disse to årende. I tillegg skal det prøves å estimere energi utbyttet fra fire forkjellige PV moduler, ved bruk av de to årene med global horisontal og vinklet spektral innstråling. Disse modulene er en c-Si modul, en a-Si modul, en CdTe modul og en CIGS modul. I utgangspunktet skulle oppgaven gå ut på å teste et håndholdt spektrometer og bli sammenlignet med et stasjonært spektrometer. Grunnet et defekt kalibrerings instrument kunne ikke dette bli undersøkt videre og hovedfokuest ble satt på spektral dataene. Et gjennomsnittlig spektral distribusjonen for hver måned ble laget untatt for månedene som manglet i data settet. Energi utbytte for de fire PV modulene ble estimert gjennom et python-skript. Energi utbyttet som ble regnet ut viste seg å være ikke riktige grunnet en feil i data prosseseringen i metode delen. Målingene til CIGS PV modulen spesifikt virket også til å være noe galt med grunnet dens høye ytelse i forhold til de andre modulene.\\ This thesis analyzes two years of global horizontal spectral irradiance and global tilted spectral irradiance data to see how the spectral distribution varies over these years. In addition, an attempt will be made to estimate the energy yield from four different PV modules using two years of global horizontal and angled spectral radiation. These modules are a c-Si module, an a-Si module, a CdTe module, and a CIGS module. Initially, the task was to test a hand-held spectrometer and be compared with a stationary spectrometer. Due to a defective calibration instrument, this could not be investigated further, and the main focus of the thesis was moved to the spectral data. An average spectral distribution for each month was created except for the months that were missing from the data set. The energy yield for the four PV modules was estimated through a Python script. The energy yield that was calculated turned out to be incorrect due to an error in the data processing in the method section. The measurements of the CIGS PV modules were also off due to their high performance compared to the other modules

1,2-Di­hydro­spiro­[carbazole-3(4H),2′-[1,3]dioxolane]

In the title compound, C14H15NO2, the hydrogenated six-membered ring of the carbazole unit adopts a half-chair conformation and the dioxolane ring points to one side of the carbazole plane. Neighbouring mol­ecules form edge-to-face inter­actions in which the NH group is directed towards an adjacent carbazole unit, with a shortest H⋯C contact of 2.72 Å. These inter­actions arrange the mol­ecules into one-dimensional herringbone-type motifs, which pack so that the methyl­ene groups of the dioxolane ring lie over the face of a neighbouring carbazole unit with a shortest H⋯C contact of 2.85 Å