Adenosine A3 receptor agonists inhibit murine macrophage tumor necrosis factor-alpha production in vitro and in vivo.

Adenosine and related analogs have been shown to regulate a variety of cell functions through different classes of adenosine receptors. Murine J774.1 macrophage cells were found to predominantly express adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA.

A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist.

Inflammation, regardless of whether it is provoked by infection or by tissue damage, starts with the activation of macrophages which initiate a cascade of inflammatory responses by producing the cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (ref. 1). Three naturally occurring ligands for the IL-1 receptor (IL1R) exist: the agonists IL-1alpha and IL-1beta and the IL-1-receptor antagonist IL1RA (ref.

The effects of antifungal agents on the morphogenetic transformation by Candida albicans in vitro.

The effects of antifungal agents, with different mechanisms of action, on the morphogenetic transformation by synchronised yeast-phase Candida albicans cells in vitro and their respective anti-Candida activities are described. MIC data demonstrated that the azoles, amphotericin B and echinocandin were the most active agents against four C. albicans strains.

Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-alpha.

Murine macrophage-derived tumor necrosis factor alpha (TNF-alpha) gene expression has been shown to be dramatically induced by bacterial lipopolysaccharide, and to be dependent upon nuclear factor-kappa B (NF-kappa B) binding sites in its promoter for the lipopolysaccharide induction. Murine J774.1 macrophage cells were found to predominantly express the adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA.

Spectrophotometric determination of the morphogenetic transformation by synchronous Candida albicans: effects of antifungal agents.

A spectrophotometric method for studying the morphogenetic transformation by Candida albicans is described. Synchronous yeast-phase C. albicans cells incubated at 35 degrees C formed germ-tubes and resulted in an absorbance increase at 340 nm but not at 595 nm.

Inhibitors of myo-inositol monophosphatase, ATCC 20928 factors A and C. Isolation, physico-chemical characterization and biological properties.

During the course of a screening program for inhibitors of myo-inositol monophosphatase we fermented the strain ATCC 20928, a known producer of L-671,776. We now show that this strain produces a complex of at least three sesquiterpenic compounds, L-671,776 (termed factor B) and two structurally related substances, termed factors A and C. Both factors A and C, like L-671,776, exhibited inhibitory activity against myo-inositol monophosphatase.

Depletion of estrogen receptor in human breast tumor cells by a novel substituted indole that does not bind to the hormone binding domain.

Steroidal antiestrogens appear to have at least two major modes of action in breast cancer cells, direct antagonism of estrogen binding to its receptor and depletion of estrogen receptors (ER) due to inhibition of dimerization of the receptor and a resultant destabilization of the receptor protein. In a search for other classes of compounds which would act as dimerization inhibitors, a novel substituted indole (8-{2-[1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-1H-indol-3-yl]-acetylamino} octanoic acid butyl-methyl amide, MDL 101,906) was synthesized. Binding of the ER to its consensus response element (ERE) was apparently decreased in nuclear extracts from MCF-7 human breast cancer cell treated with MDL 101,906.

Progression of MCF-7 breast cancer cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA-binding activity.

We have isolated a variant of the MCF-7 human breast tumor that is characterized by a hormone-independent, yet hormone-responsive, phenotype. This tumor, designated MCF-WES, was derived from MCF-7 tumor cells implanted in the mammary fat pad of a nude mouse in the absence of estradiol supplementation. MCF-WES tumors remain responsive to estradiol; however, unlike the parental MCF-7 tumors, they are stimulated to grow by tamoxifen.

Comparisons of the susceptibilities of planktonic and adherent Candida albicans to antifungal agents: a modified XTT tetrazolium assay using synchronised C. albicans cells.

Adhesion of synchronised yeast-phase Candida albicans cells to tissue culture plastic, and the susceptibility of planktonic and adherent cells to antifungal agents, was investigated using a modified tetrazolium (XTT) assay. MIC data demonstrated that ketoconazole and amphotericin B were highly active against planktonic C. albicans yeast-phase cells.

Amphiphilic alpha-tocopherol analogues as inhibitors of brain lipid peroxidation.

Neurological disorders, such as stroke, trauma, tardive dyskinesia, Alzheimer's and Parkinson's diseases, may be partially attributed to excessive exposition of the nervous tissue to oxygen-derived radicals. A novel water-soluble alpha-tocopherol analogue, 2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methylpiperazino) methyl-1-benzofuran-5-ol dihydrochloride (MDL), is a potent radical scavenger. Following subcutaneous administration to mice, MDL inhibited the lipid peroxidation induced in the 100-fold diluted brain homogenates, with an ID50 of 8 mg/kg.

Activities of novel aryloxyalkylimidazolines on rat 5-HT2A and 5-HT2C receptors.

Using transfected NIH 3T3 mouse fibroblast cell lines expressing the rat 5-HT2A and rat 5-HT2C receptor subtypes, and techniques of 2-[125I](+)-iodolysergic acid diethylamide ([125I]LSD) binding and serotonin (5-hydroxytryptamine, 5-HT)-stimulated phosphoinositide hydrolysis, we have characterized a new structural class of 5-HT receptor ligands, the aryloxyalkylimidazolines. These compounds were found to be potent competitors of [125I]LSD binding at both receptor subtypes (Ki approximately 5-200 nM) and to have efficacy ranging from potent competitive antagonists (IC50 approximately 25 nM) to moderately potent full agonists (EC50 approximately 200 nM). Some of these compounds are agonists at both receptor subtypes, while others are 5-HT2C receptor agonists with 5-HT2A receptor antagonist activity.

Antibiotics A21459 A and B, new inhibitors of bacterial protein synthesis. II. Structure elucidation.

The structures of the antibiotics, active against a few Gram-negative bacteria and Clostridium difficile, were determined on the basis of physicochemical analyses on the intact molecules and on the acid hydrolysate of A21459 A. FAB-MS and 1H and 13C NMR investigations identified the amino acid units and determined their sequence. Antibiotics A21459 A and B are homodetic cyclic peptides constituted by eight amino acid units.

Antibiotics A21459 A and B, new inhibitors of bacterial protein synthesis. I. Taxonomy, isolation and characterization.

Novel cyclic peptide antibiotics A21459 A and B are produced by a member of the genus Actinoplanes sp. These antibiotics inhibit bacterial protein synthesis and have selective antimicrobial activity against clostridia, mycoplasma and some Gram-negative bacteria.

A ribonucleotide reductase inhibitor, MDL 101,731, induces apoptosis and elevates TRPM-2 mRNA levels in human prostate tumor xenografts.

MDL 101,731, (E)2'-fluoromethylene-2'-deoxycytidine, is an irreversible inhibitor of ribonucleotide diphosphate reductase and causes regression of human tumors in nude mouse models. Messenger RNA levels for testosterone-repressed prostatic message-2 (TRPM-2), a transcript that increases in human tumor xenografts undergoing programmed cell death, were analyzed by in situ hybridization. Xenografts derived from a human prostate tumor cell line (PC-3) regressed following treatment with MDL 101,731 and the relative levels of TRPM-2 mRNA increased up to threefold in drug-treated animals.

Effects of clozapine on latent inhibition in the rat.

In the present study we have examined the effect of clozapine, an atypical antipsychotic drug, on latent inhibition (LI) using the conditioned emotional response (CER) procedure. In this procedure, ten pre-exposures to the to-be-conditioned stimulus result in weak or no LI whereas 30 pre-exposures produce robust LI. Three different experimental protocols were used to study the effects of clozapine: facilitation of LI in animals subjected to ten pre-exposures to the to-be-conditioned stimulus; antagonism of the disruptive effect of amphetamine (1mg/kg, s.

The enhancement of muscimol-stimulated 36C1 influx by the antispastic 5-aryl-3-(alkylsulfonyl)-4H-1,2,4-triazole (MDL 27,531) in rat brain membrane vesicles.

The antispastic triazole, 4-methyl-3-methylsulphonyl-5-phenyl-4H-1,2,4-triazole (MDL 27,531) was tested in glycine- and muscimol-stimulated 36Cl- influx into brain membrane preparations. MDL 27,531 (100 nM) had no effect on glycine- (100 nM-400 microM) stimulated 36Cl- influx in brain stem tissue; on the other hand, MDL 27,531 (10 nM-10 microM) enhanced muscimol- (1 microM) stimulated 36Cl- influx in cerebellar but not cortical membranes. In the presence of the benzodiazepine (BZD) antagonist, flumazenil (10 microM), MDL 27,531 inhibited muscimol-stimulated flux.

MDL 29311, a phenolic antioxidant, interferes with the interaction of apoC with VLDL: a possible explanation for its triglyceride-lowering effect.

MDL 29311 is an antioxidant that lowers plasma triglycerides and raises high density lipoprotein (HDL) cholesterol in rats. It lowers triglycerides in rats by enhancing the clearance of very low density lipoprotein (VLDL) by the liver (Sheetz, M. J.

Analysis of (R)-4-oxo-5-phosphononorvaline (MDL 100,453) in rat plasma and brain dialysate using liquid chromatography after derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate.

A liquid chromatographic (LC) method with precolumn derivatization and fluorescence detection has been developed for the quantitation of (R)-4-oxo-5-phosphononorvaline (MDL 100,453), which is a selective antagonist of N-methyl-D-aspartate receptor, in rat plasma and brain dialysate. The plasma samples were deproteinized with acetonitrile and then derivatized with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC). The brain dialysis samples were dried in vacuum, reconstituted with borate buffer, and derivatized with AQC.

In-vitro activity of purpuromycin and MDL 63,604 against microorganisms that cause vaginitis and vaginosis.

Purpuromycin and its semi-synthetic derivative MDL 63,604 had in-vitro activity similar to that of amphotericin B against isolates of Candida albicans. MDL 63,604 had activity similar to that of metronidazole against Trichomonas vaginalis. Both compounds were very active against most species of Gram-positive and Gram-negative anaerobes and against Gardnerella vaginalis.

Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor 2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone in dog. Potential for transdermal patch delivery.

MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone, CAS 132236(18-1) is a novel tight-binding inhibitor of acetylcholinesterase (AChE), which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer's disease. Pharmacokinetics and pharmacodynamics of the compound were studied in the dog after single intravenous (i.v.

Pharmacological evaluation of selected, orally active, peptidyl inhibitors of human neutrophil elastase.

Human neutrophil elastase (HNE) is a serine proteinase capable of degrading a number of connective tissue macromolecules and has been implicated in the destructive processes associated with several chronic inflammatory diseases. A large series of peptidyl electrophilic ketones have been shown to be potent inhibitors of HNE in vitro and in vivo. We report the pharmacology and pharmacokinetics of selected inhibitors from this series.

Antibiotic GE37468 A: a novel inhibitor of bacterial protein synthesis. II. Structure elucidation.

GE37468 A is a novel antibiotic produced by Streptomyces sp. ATCC 55365. It has molecular mass 1309.

Polymorphism in the beta chain of IAq versus IAp influences presentation of protein but not peptide antigens.

T cells play a critical role in the development of collagen-induced arthritis (CIA). Immunization with heterologous (chick) type II collagen (cII) results in chronic inflammation with progressive damage to the joints. The expression of specific MHC Class II alpha beta dimers, including IAq, is critical to induction of disease.