We have synthesized iodinated resiniferatoxin bearing a 4-hydroxy-5-iodo-3-methoxyphenylacetate ester (I-RTX) and have characterized its activity on rat and human TRPV1 (VR1) receptors, as well as in behavioral assays of nociception. In whole cell patch-clamp recordings from transfected cells the functional activity of I-RTX was determined. Currents activated by capsaicin exhibited characteristic outward rectification and were antagonized by capsazepine and I-RTX. On rat TRPV1 the affinity of I-RTX was 800-fold higher than that of capsazepine (IC 50 ϭ 0.7 and 562 nM, respectively) and 10-fold higher on rat versus human receptors (IC 50 ϭ 0.7 and 5.4 nM, respectively). The same difference was observed when comparing the inhibition of [ 3 H]RTX binding to rat and human TRPV1 membranes for both RTX and I-RTX. Additional pharmacological differences were revealed using protons as the stimulus. Under these conditions capsazepine only partly blocked currents through rat TRPV1 receptors (by 70 to 80% block), yet was a full antagonist on human receptors. In contrast, I-RTX completely blocked proton-induced currents in both species and that activated by noxious heat. I-RTX also blocked capsaicin-induced firing of C-fibers in a rat in vitro skin-nerve assay. Despite this activity and the high affinity of I-RTX for rat TRPV1, only capsazepine proved to be an effective antagonist of capsaicin-induced paw flinching in rats. Thus, although I-RTX has limited utility for in vivo behavioral studies it is a high-affinity TRPV1 receptor antagonist that will be useful to characterize the functional properties of cloned and native vanilloid receptor subtypes in vitro.The transient receptor potential TRPV1 vanilloid receptor (also known as VR1; see revised TRP channel nomenclature Montell et al., 2002) gates a nonselective cation channel that is expressed by sensory neurons and that can be activated by protons, heat, and capsaicin, the pungent ingredient of chili peppers (Caterina et al., 1997;Tominaga et al., 1998). Ligands acting at the TRPV1 vanilloid receptor subtype have the potential therapeutic utility to treat thermal hyperalgesia-related pain and some inflammatory conditions (for review, see Szallasi and Blumberg, 1999;Caterina and Julius, 2001). One of the first antagonists described for the capsaicin receptor was capsazepine (Bevan et al., 1992). This ligand has been used widely to explore the functional significance of TRPV1 receptors in pain. However it has relatively low micromolar affinity for TRPV1 receptors and because it also blocks voltage-gated calcium channels, this has made interpretation of functional data with this compound less straightforward (Docherty et al., 1997).To date, one of the highest affinity ligands reported for the TRPV1 receptor is the natural plant product resiniferatoxin (RTX), which was first isolated from Euphorbia resinifera (Szallasi and Blumberg, 1989). Interestingly, it has been shown recently that iodination of this agonist RTX confers antagonist-like properties to the ligand wit...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1b, by central and peripheral immune cells. Il-1b has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS• Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/ pharmacodynamic model for LPS-stimulated ATP-induced Il-1b production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. AIMSThis paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODSEscalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1b production in blood were evaluated. RESULTSDrug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1b as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n = 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSIONThe model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development.

Bacteriophages or phages, being the most abundant entities on earth, represent a potential solution to a diverse range of problems. Phages are successful antibacterial agents whose use in therapeutics was hindered by the discovery of antibiotics. Eventually, because of the development and spread of antibiotic resistance among most bacterial species, interest in phage as therapeutic entities has returned, because their noninfectious nature to humans should make them safe for human nanomedicine.This review highlights the most recent advances and progress in phage therapy and bacterial hosts against which phage research is currently being conducted with respect to food, human, and marine pathogens. Bacterial immunity against phages and tactics of phage revenge to defeat bacterial defense systems are also summarized.We have also discussed approved phage-based products (whole phage-based products and phage proteins) and shed light on their influence on the eukaryotic host with respect to host safety and induction of immune response against phage preparations.Moreover, creation of phages with desirable qualities and their uses in cancer treatment, vaccine production, and other therapies are also reviewed to bring together evidence from the scientific literature about the potentials and possible utility of phage and phage encoded proteins in the field of therapeutics and industrial biotechnology.

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Strigolactones (SLs), being a new class of plant hormones, play regulatory roles against abiotic stresses in plants. There are multiple hormonal response pathways, which are adapted by the plants to overcome these stressful environmental constraints to reduce the negative impact on overall crop plant productivity. Genetic modulation of the SLs could also be applied as a potential approach in this regard. However, endogenous plant hormones play central roles in adaptation to changing environmental conditions, by mediating growth, development, nutrient allocation, and source/sink transitions. In addition, the hormonal interactions can fine-tune the plant response and determine plant architecture in response to environmental stimuli such as nutrient deprivation and canopy shade. Considerable advancements and new insights into SLs biosynthesis, signaling and transport has been unleashed since the initial discovery. In this review we present basic overview of SL biosynthesis and perception with a detailed discussion on our present understanding of SLs and their critical role to tolerate environmental constraints. The SLs and abscisic acid interplay during the abiotic stresses is particularly highlighted.Main Conclusion: More than shoot branching Strigolactones have uttermost capacity to harmonize stress resilience.