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Concept: Ligand


The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CL(tot)/F) and renal clearance (CL®) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CL(tot)/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CL(tot)/F of fexofenadine enantiomers, whereas the stereoselectivity in the CL® persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1)-mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses.

Concepts: Pharmacology, Human, Receptor, Ligand, Histamine, Receptor antagonist, Inverse agonist, Histamine H1 receptor


The G-quadruplex ligands database (G4LDB, provides a unique collection of reported G-quadruplex ligands to streamline ligand/drug discovery targeting G-quadruplexes. G-quadruplexes are guanine-rich nucleic acid sequences in human telomeres and gene promoter regions. There is a growing recognition for their profound roles in a wide spectrum of diseases, such as cancer, diabetes and cardiovascular disease. Ligands that affect the structure and activity of G-quadruplexes can shed light on the search for G-quadruplex-targeting drugs. Therefore, we built the G4LDB to (i) compile a data set covering various physical properties and 3D structure of G-quadruplex ligands; (ii) provide Web-based tools for G-quadruplex ligand design; and (iii) to facilitate the discovery of novel therapeutic and diagnostic agents targeting G-quadruplexes. G4LDB currently contains >800 G-quadruplex ligands with ∼4000 activity records, which, to our knowledge, is the most extensive collection of its kind. It offers a user friendly interface that can meet a variety of data inquiries from researchers. For example, ligands can be searched for by name, molecular properties, structures, ligand activities and so on. Building on the reported data, the database also provides an online ligand design module that can predict ligand binding affinity in real time.

Concepts: DNA, Gene, Cancer, Promoter, Ligand, RNA polymerase, G-quadruplex, Telomere


Binding of cellular α-dystroglycan (α-DG) to its extracellular matrix ligands is fully dependent on a unique O-mannose-linked glycan. Disrupted O-mannosylation is the hallmark of the muscular dystrophy-dystroglycanopathy (MDDG) syndromes. SLC35A1, encoding the transporter of CMP-sialic acid, was recently identified as MDDG candidate gene. This is surprising, since sialic acid itself is dispensable for α-DG-ligand binding. In a novel SLC35A1-deficient cell model, we demonstrated a lack of α-DG O-mannosylation, ligand binding and incorporation of sialic acids. Removal of sialic acids from HAP1 wild type cells after incorporation or preventing sialylation during synthesis did not affect α-DG O-mannosylation or ligand binding but did affect sialylation. Lentiviral-mediated complementation with the only known disease mutation p.Q101H failed to restore deficient O-mannosylation in SLC35A1 knockout cells and partly restored sialylation. These data indicate a role for SLC35A1 in α-DG O-mannosylation that is distinct from sialic acid metabolism. In addition, human SLC35A1 deficiency can be considered as a combined disorder of α-DG O-mannosylation and sialylation, a novel variant of the MDDG syndromes.

Concepts: DNA, Protein, Gene, Amine, Ammonia, Sialic acid, Ligand, Jason Statham


Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential-reinforcement-of-low-rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone, ghrelin, increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity.Neuropsychopharmacology accepted article preview online, 01 October 2015. doi:10.1038/npp.2015.297.

Concepts: Hormone, Receptor, Ligand, Receptor antagonist, Inverse agonist, Dopamine, Reward system, Ghrelin


The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease. But there is still a hard core of patients who do not tolerate or benefit from existing therapies and who require effective treatment. Novel approaches include the use of currently available drugs off-licence, investigational drugs currently undergoing clinical trials and exploring the potential for therapies directed at pathophysiological targets in CSU. Off-licence uses of currently available drugs include rituximab and tumour necrosis factor inhibitors. Ligelizumab (anti-IgE), canakinumab (anti-IL-1), AZD1981 (a PGD2 receptor antagonist) and GSK 2646264 (a selective Syk inhibitor) are currently in clinical trials for CSU. Examples of drugs that could target potential pathophysiological targets in CSU include substance P antagonists, designed ankyrin repeat proteins, C5a/C5a receptor inhibitors, anti-IL-4, anti-IL-5 and anti-IL-13 and drugs that target inhibitory mast cell receptors. Other mediators and receptors of likely pathogenic relevance should be explored in skin profiling and functional proof of concept studies. The exploration of novel therapeutic targets for their role and relevance in CSU should help to achieve a better understanding of its etiopathogenesis.

Concepts: Protein, Medicine, Signal transduction, Receptor, Ligand, Receptor antagonist, Inverse agonist, Schild regression


Humans' core body temperature (CBT) is strictly controlled within a narrow range. Various studies dealt with the impact of physical activity, clothing, and environmental factors on CBT regulation under terrestrial conditions. However, the effects of weightlessness on human thermoregulation are not well understood. Specifically, studies, investigating the effects of long-duration spaceflight on CBT at rest and during exercise are clearly lacking. We here show that during exercise CBT rises higher and faster in space than on Earth. Moreover, we observed for the first time a sustained increased astronauts' CBT also under resting conditions. This increase of about 1 °C developed gradually over 2.5 months and was associated with augmented concentrations of interleukin-1 receptor antagonist, a key anti-inflammatory protein. Since even minor increases in CBT can impair physical and cognitive performance, both findings have a considerable impact on astronauts' health and well-being during future long-term spaceflights. Moreover, our findings also pinpoint crucial physiological challenges for spacefaring civilizations, and raise questions about the assumption of a thermoregulatory set point in humans, and our evolutionary ability to adapt to climate changes on Earth.

Concepts: Receptor, Thermoregulation, Ligand, Receptor antagonist, Space exploration, Schild regression, Spaceflight, Normal human body temperature


Montelukast, a selective leukotriene receptor antagonist, is recommended in guidelines for the treatment of asthma in both children and adults. However, its effectiveness is debated, and recent studies have reported several adverse events such as neuropsychiatric disorders and allergic granulomatous angiitis. This study aims to obtain more insight into the safety profile of montelukast and to provide prescribing physicians with an overview of relevant adverse drug reactions in both children and adults. We retrospectively studied all adverse drug reactions on montelukast in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global database, VigiBase(®) until 2016. Depression was reported most frequently in the whole population to the global database VigiBase(®) (reporting odds ratio (ROR) 6.93; 95% CI: 6.5-7.4). In the VigiBase(®) , aggression was reported the most in children (ROR, 29.77; 95% CI: 27.5-32.2). Headaches were reported the most frequently to the Dutch database (ROR, 2.26; 95% CI: 1.61-3.19). Furthermore, nightmares are often reported for both children and adults to the Dutch and the global database. Eight patients with allergic granulomatous angiitis were reported to the Dutch database and 563 patients in the VigiBase(®) . These data demonstrate that montelukast is associated with neuropsychiatric adverse drug reactions such as depression and aggression. Especially in children nightmares are reported frequently. Allergic granulomatous angiitis is also reported, a causal relationship has not been established.

Concepts: Pharmacology, Asthma, Receptor, Ligand, Receptor antagonist, Adverse drug reaction, Netherlands, Leukotriene


Female mosquitoes that transmit deadly diseases locate human hosts by detecting exhaled CO2 and skin odor. The identities of olfactory neurons and receptors required for attraction to skin odor remain a mystery. Here, we show that the CO2-sensitive olfactory neuron is also a sensitive detector of human skin odorants in both Aedes aegypti and Anopheles gambiae. We demonstrate that activity of this neuron is important for attraction to skin odor, establishing it as a key target for intervention. We screen ∼0.5 million compounds in silico and identify several CO2 receptor ligands, including an antagonist that reduces attraction to skin and an agonist that lures mosquitoes to traps as effectively as CO2. Analysis of the CO2 receptor ligand space provides a foundation for understanding mosquito host-seeking behavior and identifies odors that are potentially safe, pleasant, and affordable for use in a new generation of mosquito control strategies worldwide. PAPERCLIP:

Concepts: Mosquito, Receptor, Cell signaling, Ligand, Receptor antagonist, Aedes aegypti, Aedes, Ligand-gated ion channel


Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5) carrying a Cre-dependent channelrhodopsin-2 (ChR2)-enhanced yellow fluorescent protein (eYFP) expression cassette under the control of the two neuronal POMC enhancers (nPEs). Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.

Concepts: Nervous system, Protein, Hypothalamus, Signal transduction, Receptor, Ion channel, Ligand, Receptor antagonist


Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug’s release, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesia in vivo using a photocaged mGlu5 receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders.

Concepts: Nervous system, Energy, Light, Ligand, Pain, Metabotropic receptor, Light-emitting diode, Lighting