GPR18 Inhibiting Amauromine and the Novel Triterpene Glycoside Auxarthonoside from the Sponge-Derived Fungus Auxarthron reticulatum.

The marine sponge-derived fungus Auxarthron reticulatum produces the cannabinoid receptor antagonist amauromine (1). Recultivation of the fungus to obtain further amounts for more detailed pharmacological evaluation of 1 additionally yielded the novel triterpene glycoside auxarthonoside (2), bearing, in nature, a rather rare sugar moiety, i.e.

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors.

Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species.

Deciphering the Epigenetic Code of Cardiac Myocyte Transcription.

Rationale: Epigenetic mechanisms are crucial for cell identity and transcriptional control. The heart consists of different cell types, including cardiac myocytes, endothelial cells, fibroblasts, and others. Therefore, cell type-specific analysis is needed to gain mechanistic insight into the regulation of gene expression in cardiac myocytes.

Dual target strategy: combining distinct non-dopaminergic treatments reduces neuronal cell loss and synergistically modulates L-DOPA-induced rotational behavior in a rodent model of Parkinson's disease.

The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2A R) represent major non-dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6-hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), and two A2A R antagonists, (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl]propyl] (MSX-3) and 8-ethoxy-9-ethyladenine (ANR 94). Chronic treatment with MPEP or MSX-3 alone, but not with ANR 94, reduced the toxin-induced loss of dopaminergic neurons in the substantia nigra pars compacta.

Competitive mode and site of interaction of ticagrelor at the human platelet P2Y12 -receptor.

Background: The G-protein-coupled P2Y12 -receptor plays a crucial role in platelet aggregation. Recently, ticagrelor was licensed as the first perorally active and reversible P2Y12 -receptor antagonist.

Objective: The present study investigated the site and the antagonistic mode of action of ticagrelor at wild-type or mutant human P2Y12 -receptors.

Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease.

The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation,is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.

Inhibitory effects of benzodiazepines on the adenosine A(2B) receptor mediated secretion of interleukin-8 in human mast cells.

The activation of adenosine A(2B) receptors in human mast cells causes pro-inflammatory responses such as the secretion of interleukin-8. There is evidence for an inhibitory effect of benzodiazepines on mast cell mediated symptoms in patients with systemic mast cell activation disease. Therefore, we investigated the effects of benzodiazepines on adenosine A(2B) receptor mediated interleukin-8 production in human mast cell leukaemia (HMC1) cells by an enzyme linked immunosorbent assay.

Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells.

Defects in intracellular accumulation of the antitumour drug cisplatin are a commonly observed feature in the cells selected for cisplatin resistance. Copper transporter 1 (CTR1) has been suggested to play an important role in drug uptake and resistance. Here, we describe a detailed investigation of the involvement of CTR1 in cisplatin uptake and its relevance for cisplatin resistance using a well characterised sensitive/cisplatin-resistant cell line pair: A2780 human ovarian carcinoma cell line and its cisplatin-resistant variant A2780cis.

Identification of a Potent and Selective Cannabinoid CB1 Receptor Antagonist from Auxarthron reticulatum.

The fungus Auxarthron reticulatum derived from the marine sponge Ircinia variabilis produced the diketopiperazine alkaloid amauromine (1) and the quinolinone methyl-penicinoline (2). Compound 2 is identical to the reported methyl-marinamide, whose structure is herewith revised. In radioligand binding studies at human cannabinoid CB1 and CB2 receptors recombinantly expressed in Chinese hamster ovary (CHO) cells, amauromine (1) was found to exhibit high affinity and selectivity for the CB1 receptor (K i = 178 nM).

Synthesis and properties of a new water-soluble prodrug of the adenosine A 2A receptor antagonist MSX-2.

The compound L-valine-3-{8-[(E)-2-[3-methoxyphenyl)ethenyl]-7-methyl-1-propargylxanthine-3-yl}propyl ester hydrochloride (MSX-4) was synthesized as an amino acid ester prodrug of the adenosine A2A receptor antagonist MSX-2. It was found to be stable in artificial gastric acid, but readily cleaved by pig liver esterase.

Efficacy of a pelargonium sidoides preparation in patients with the common cold: a randomized, double blind, placebo-controlled clinical trial.

Background: The common cold is a viral infection with symptoms such as sneezing, sore throat, and running nose. It is one of the most prevalent illnesses in the world, and although commonly caused by rhinoviruses, antibiotics are often prescribed unnecessarily. Therefore, it is of utmost importance to evaluate alternative treatments such as herbal medications, whose efficacy and safety is proven by pharmacological and clinical studies.

The applications of biomarkers in early clinical drug development to improve decision-making processes.

Selecting and evaluating biomarkers in drug discovery and early drug development can substantially shorten clinical development time or the time to reach a critical decision point in exploratory drug development. Critical decisions such as candidate selection, early proof of concept/principle, dose ranging, development risks, and patient stratification are based on the appropriate measurements of biomarkers that are biologically and/or clinically validated. The use of biomarkers helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects and will increase the success rate in the confirmatory stage of clinical development.

Photo-chemically induced DNA effects in the comet assay with epidermal cells of SKH-1 mice after a single oral administration of different fluoroquinolones and 8-methoxypsoralen in combination with exposure to UVA.

Unlabelled: Due to the need for in vivo photo-genotoxicity tests, the in vivo photo-comet assay was established in epidermal cells of the SKH-1 mouse. Groups of 10 male SKH-1 mice each were treated once orally with vehicle only, with three fluoroquinolones (25 mg/kg clinafloxacin, 20 mg/kg lomefloxacin, 200 mg/kg ciprofloxacin) or with 200mg/kg 8-methoxypsoralene (8-MOP). Thirty minutes after treatment half of the mice in each group were exposed to 23.

Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir.

Objective: To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir.

Design: Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group).

Silver nanoparticle enhanced immunoassays: one step real time kinetic assay for insulin in serum.

Silver nanoparticle enhanced fluorescence is introduced as an alternative method to surface plasmon resonance techniques for real time monitoring of biorecognitive interactions or immunoassays. This method relies on the phenomenon that an electromagnetic near field is generated upon illumination on the surface of silver nanoparticles. The interaction of this field with nearby fluorophores results in fluorescence enhancement.

Stabilisation and determination of the biological activity of L-asparaginase in poly(D,L-lactide-co-glycolide) nanospheres.

The preservation of biological activity of protein drugs in formulations is still a major challenge for successful drug delivery. The enzyme L-asparaginase, which exhibits a short in vivo half-life and is only active against leukaemia in its tetrameric form, was encapsulated in poly(D,L-lactide-co-glycolide) nanospheres by the (w/o)/w-emulsion solvent evaporation technique in presence of various potential stabilisers. Elucidation of the preparation steps revealed that the enzyme is denaturated at the aqueous/organic interface and by sonication.

Sesquiterpenes and flavonoid aglycones from a Hungarian taxon of the Achillea millefolium group.

The investigation of a dichloromethane extract of flower heads of a Hungarian taxon of the Achillea millefolium group led to the isolation of three flavonoid aglycones, one triterpene, one germacranolide and five guaianolides. Their structures were elucidated by UV-VIS, EI- and CI-MS, 1H NMR and 13C NMR spectroscopic methods as well as by 2D-NMR studies and by selective 1D-NOE experiments. Besides apigenin, luteolin and centaureidin, beta-sitosterol, 3beta-hydroxy-11alpha,13-dihydro-costunolide, desacetylmatricarin, leucodin, achillin, 8alpha-angeloxy-leucodin and 8alpha-angeloxy-achillin were isolated.