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Biomedical subjects

A Monge

Publications and source records attributed to A Monge.

At least 37 records · Page 2Linked to original sources
PubMed2000

A new NPY-antagonist strongly stimulates apoptosis and lipolysis on white adipocytes in an obesity model.

Neuropeptide Y (NPY) is a 36 amino acid peptide released in central and peripheral mammalian neurons, which appears to contribute to adiposity regulation by increasing food intake, thus promoting weight gain on animals. Nevertheless, little is known about NPY direct actions on white adipocytes. This trial, which was designed to test the possible effects of a new NPY antagonist, S.A.0204, on white adipose tissue, revealed that the administration of this novel molecule strongly ex vivo stimulates apoptosis and lipolysis in animals fed on a high-fat diet.

Adipocytes↗
PubMed2000

Substitution and hydrogenation reactions on rhodium(I)-ethylene complexes of the hydrotris(pyrazolyl)borate ligands T (T = Tp, TpMe2).

The bis(ethylene) Rh species TpMe2Rh(C2H4)2(1*) (TpMe2 = tris(3,5-dimethyl-1-pyrazol-1-yl)hydroborate) has been obtained from [RhCl(C2H4)2]2 and KTpMe2. Complex 1* easily decomposes in solution to give mainly the butadiene species TpMe2Rh(eta74-C4H6). In the solid state its thermal decomposition follows a different course and the allyl TpMe2RhH(syn-C3H4Me) is cleanly obtained as a mixture of exo and endo isomers. The complexes Tp'Rh(C2H4)2 (Tp' = Tp, TpMe2) afford the monosubstituted species Tp'Rh(C2H4)(PR3) upon reaction with PR3 but react differently with L = CO or CNR: the Tp compound gives dinuclear [TpRh]2(mu-L)3 complexes, while, in the case of 1*, TpMe2Rh(C2H4)(L) species are obtained. The ethylene ligand of complexes TpMe2Rh(C2H4)(PR3) is labile, and several peroxo compounds of composition TpMe2Rh(O2)(PR3) have been isolated by their reaction with O2. All the mononuclear Rh(I) complexes are formulated as 18e- trigonal bipyramidal species on the basis of IR and NMR spectroscopic studies. A series of dihydride complexes of Rh(III) of formulation Tp'RhH2(PR3) have been prepared by the hydrogenation of the corresponding ethylene derivatives. Complexes [TpRh]2(mu-CNCy)3, TpMe2Rh(C2H4)(PEt3), and TpMe2Rh(O2)(PEt3) have been further characterized by X-ray diffraction studies.

Journal Article↗
PubMed2000

Synthesis and biological evaluation of 1,2,5-oxadiazole N-oxide derivatives as potential hypoxic cytotoxins and DNA-binders.

Several new 1,2,5-oxadiazole N-oxide derivatives were synthesized to be tested both as potential selective hypoxic cell cytotoxins and as DNA-binding agents. The compounds prepared included bis(1,2,5-oxadiazole N-oxide) derivatives and oxadiazole rings linked to naphthyl residues. The compounds were tested for their cytotoxicity in oxia and hypoxia and they proved to be non-selective and less active than the parent compounds 3-formyl-4-phenyl-1,2,5-oxadiazole N2-oxide (3) and 3-chloromethyl-4-phenyl-1,2,5-oxadiazole N2-oxide (4). The DNA-affinity assays showed that the compounds tested have poor affinity for this biomolecule.

Aerobiosis↗
PubMed2000

Design, synthesis and biological evaluation of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives as potential antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT1A receptor antagonism.

It has been suggested that the combination of a selective serotonin reuptake inhibitor (SSRI) and a 5-HT1A receptor antagonist may facilitate the onset of the SSRIs antidepressant action. Accordingly, we describe the synthesis of a series of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives with structural modifications performed in Ar1, Ar2 and Z (Z is different functional groups) to obtain the sought dual activity. Compounds were evaluated for in vitro affinity at 5-HT1A receptors and 5-HT transporter. The antidepressant-like activity of derivatives with the higher affinity was assessed initially using the forced swimming test (FST). Compound 1-(2,4-dimethylphenyl)-3-[(2-methoxyphenyl)piperazin-1-il]-1-propa none (III.1.a) showed the best antidepressant-like activity which was further confirmed in the learned helplessness test.

Animals↗
PubMed2000

University education of medicinal chemists: comparison of eight countries.

Medicinal chemists are mainly taught in faculties or schools of pharmacy and are available for employment. Yet major pharmaceutical research companies seek organic chemists, rather than medicinal chemists, for new drug discovery. This apparent contradiction led the Medicinal Chemistry Section of IUPAC to send a questionnaire regarding postgraduate academic education for medicinal chemists to the faculties or schools of pharmacy in eight countries, namely, France, Germany, Italy, Japan, Spain, Switzerland, UK and USA. The questionnaire aimed to elicit information about postgraduate medicinal chemistry students, their courses and training, and the occupations taken up after graduation. The replies representing 109 medicinal chemistry departments or sections have been analysed and the results are presented to provide a data base on modern medicinal chemistry curricula for comparative purposes. The information should help guide discussion of the optimum paths to be followed by students in preparation for their careers. The evidence suggests that academic training of medicinal chemists equips them to enter a wide range of occupations, many of which are in industry.

Chemistry, Organic↗
PubMed2000

New quinoxalinecarbonitrile 1,4-di-N-oxide derivatives as hypoxic-cytotoxic agents.

We report the synthesis and biological in vitro activities of 16 new 2-quinoxalinecarbonitrile 1,4-di-N-oxides. These compounds present new basic lateral chains (piperazines and anilines) in the 3 position as well as different substituents in the 6 and/or 7 positions of the quinoxaline ring. Among piperazine derivatives, 4b (a 7-chloro-3-(4-methylpiperazin-1-yl) derivative) was the most potent (P = 0.5 x10(-6) M). In general, aniline derivatives were more potent and selective than the former, compound 12b (with a 4-(methylphenyl)amino moiety in the 3 position and a chlorine atom in the 7 position) being the best one (P = 3 x 10(-6) 16).

Animals↗
PubMed2000

Medicinal chemistry in the development of societies. Biodiversity and natural products.

This document has been elaborated by the IUPAC Medicinal Chemistry section and is backed by a large number of scientists, many of whom have had direct involvement and whose names appear at the end of the article. This work discusses the role that the discovery of new medicinal agents has in the development of societies as well as in the conservation of biodiversity in terms of work carried out on natural products. Also included are several recommendations for countries which are presently in search of their own scientific and technological development in medicinal agents. The IUPAC Medicinal Chemistry section would appreciate the collaboration of the scientific societies in every country to aid in the diffusion of this document.

Biological Products↗
PubMed2000

New antiherpetic 1,3-phenylene derivatives, inhibitors of the interaction of the HSV-1 origin binding protein (OBP) with DNA.

The synthesis of new 1,3-phenylene derivatives and their preliminary evaluation as antivirals (Herpes simplex 1, HSV-1) whose antiherpetic activity can be related with the inhibition of the interaction of the origin binding protein (OBP) with the DNA are presented. The new compounds are adjusted to a previously defined common structural model, consisting of a central aromatic system, which presents two side chains of different lengths in relative position 1, 3; these chains are made up of atomic groups characterized by the alternation of positive and negative centers, situating differently substituted rings, preferably aromatic, at the ends of both chains. Some of these derivatives, such as N,N''-(4-methoxy-1,3-phenylene)bis[N'-(4-nitrophenyl)urea] (2c) or (1,3-phenylene)bis[N-(p-tolyl)aminosulfonyl] (11b), show antiherpetic activity related to the proposed mechanism.

Animals↗
PubMed1999

Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles.

A set of new pyrimido[5,4-b]indole derivatives that are structurally related to some non-nucleside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1IIIB cells. Preliminary structure-activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy.

Anti-HIV Agents↗
PubMed1999

Argentine plant extracts active against polymerase and ribonuclease H activities of HIV-1 reverse transcriptase.

Lipophilic and hydrophilic extracts of four Argentine plants (Gamochaeta simplicaulis Cabr. 1, Achyrocline flaccida Wein. D. C. 2, Eupatorium buniifolium H. et A. 3, and Phyllanthus sellowianus Muell. Arg. 4) were examined in vitro for their ability to inhibit the polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) (wild and Y181C mutant types). The active extracts were also examined as inhibitors of viral replication in HLT4LacZ-1IIIB cell cultures, evaluating their cytotoxicity in parallel. Infusions 2I and 4I, among the crude extracts, showed the highest activity. These extracts were refractioned into four fractions; 2I4 and 4I4 were active as inhibitors of DNA-polymerase (wild and Y181C types) and RNase H activities. These fractions were potent as inhibitors of viral replication and were not cytotoxic. Refractionation of 2I4 yielded five new fractions, two of which, 2I4-4 and 2I4-5, showed notable activity. Refractionation of 4I4 yielded for new fractions; of these, 4I4-3 and 4I4-4 were active. The marked biological activity found in the infusion of A. flaccida and P. sellowianus makes them sufficiently attractive to be considered in the combined chemotherapy of the disease.

Anti-HIV Agents↗
PubMed1999

New quinoxaline 1,4-di-N-oxides for treatment of tuberculosis.

Some quinoxaline 1,4-di-N-oxides derivatives with very different substituents in 2, 3, 6 and 7 positions have been synthesized in order to obtain new hypoxia selective agents. Some of these products have been tested as antituberculosis agents and very interesting results have been obtained from the first screening.

Antibiotics, Antitubercular↗
PubMed1999

Synthesis and antituberculosis activity of new 2-quinoxalinecarbonitrile 1,4-di-N-oxides.

With the advent of multidrug-resistant Mycobacterium tuberculosis strains, new and effective therapies are rapidly needed to combat infections caused by these strains. Some new 2-quinoxalinecarbonitrile 1,4-di-N-oxides have been synthesized and tested as antituberculosis agents and interesting results have been obtained from the first screening.

Antitubercular Agents↗
PubMed1997

Determination of apomorphine in human plasma by alumina extraction and high-performance liquid chromatography with electrochemical detection.

Apomorphine is a powerful agonist of dopaminergic receptors which several years ago was introduced into the therapy of Parkinson's Disease. The pharmacological activity of apomorphine already appears significant at low doses. Unfortunately, the difficulty in determining the drug in plasma at low concentrations hampers the completion of accurate pharmacokinetic studies in humans. Considering the analogy of apomorphine with the molecular structure of catecholamines, the extraction of the drug from plasma was optimized by using adsorption on alumina, a technique widely used for noradrenaline and adrenaline analysis in clinical chemistry laboratories. This method proved particularly efficient and selective in apomorphine extraction from plasma prior to high-performance liquid chromatographic analysis. After pretreatment of 200 microliters of plasma sample with 40 mg of alumina and 10 microliters of tris buffer (pH 8.6), the drug was eluted with 200 microliters of an acidic-organic solution. One volume of the supernatant was mixed with two volumes of phosphate buffer (pH 3.6), and 100 microliters of the obtained mixture were injected into the HPLC system. The chromatograph was equipped with a C18 reversed-phase column and with an electrochemical coulometric detector fitted with a high-sensitivity cell (first electrode 0.00 volts, second electrode +0.35 volts). Sensitivity (20 pg of injected drug), precision (CV within assay and between assays of 3.7% and 5.6%, respectively) and accuracy were comparable to more complex analytical procedures. The miniaturisation of the entire sample pretreatment proved very advantageous for pharmacokinetics studies and, in principle, for therapeutic drug monitoring and toxicological investigations.

Adsorption↗
PubMed1997

Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy volunteers.

Interleukin-10 inhibits T-lymphocyte activation and proliferation and lipopolysaccharide-induced monocyte production of proinflammatory cytokines. Fifty-four healthy volunteers received single doses of recombinant human interleukin-10 (1.0, 2.5, 5.0, 10, 25, or 50 micrograms/kg) or placebo by subcutaneous injection (randomized double-blind assignment). Clinical adverse events were infrequent at doses below 50 micrograms/kg (five of six subjects had mild flu-like syndrome). Mean serum interleukin-10 concentrations were dose related. The mean terminal-phase half-life ranged from 2.7 to 4.5 hours, and the apparent volume of distribution ranged from 0.70 to 1.35 L/kg. Hematologic changes included transient mild to moderate increases of neutrophil counts, decreases of lymphocyte counts, and a delayed decrease of platelet counts. Recombinant human interleukin-10 significantly suppressed production of the proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha by whole blood stimulated ex vivo with Escherichia coli lipopolysaccharide.

Adult↗
PubMed1997

The long-duration action of levodopa may be due to a postsynaptic effect.

A single dose of levodopa (L-DOPA) reduces motor disability in Parkinson's disease (PD) for a few hours, a short-duration effect. However, there are suggestions that L-DOPA may also produce a long-duration benefit of some days. In the present study, we examined the long-duration action of L-DOPA by observing the time taken to achieve maximum stable benefit after starting a constant dose of sinemet-CR (sinemet-CR) (200 g L-DOPA/50 mg carbidopa) twice daily in nine newly diagnosed patients, and the time taken to deteriorate back to baseline after stopping treatment. A single dose of sinemet-CR (200 mg L-DOPA/50 mg carbidopa) had little obvious short-duration action on the Unified PD Rating Scale (UPDRS) motor scores in the majority of patients, either before starting chronic sinemet-CR therapy (200 mg L-DOPA/50 mg carbidopa, b.i.d.) or after chronic treatment. However, all patients gradually improved on chronic sinemet-CR therapy, taking 9.3 +/- 1.8 days to achieve maximum response. On stopping chronic sinemet-CR treatment, it took 6.8 +/- 3.0 days for the same patients to deteriorate back to baseline motor disability. In similar experiments, the time taken to deteriorate back to baseline after stopping treatment with the directly acting dopamine agonist ropinirole (9-21 mg daily) in eight other de novo patients with PD was found to be 6.2 +/- 1.7 days. The long-duration effect of L-DOPA and ropinirole may, therefore, be due to some slowly evolving postsynaptic pharmacodynamic change in the central nervous system (CNS). Loss of this long-duration action may be responsible for the emergence of motor fluctuations on chronic L-DOPA therapy.

Adult↗
PubMed1997

VB20B7, a novel 5-HT-ergic agent with gastrokinetic activity. I. Interaction with 5-HT3 and 5-HT4 receptors.

This study describes the in-vitro interaction of the gastrokinetic agent 2[1-(4-piperonyl)piperazinyl]benzothiazole (VB20B7) with the 5-hydroxytryptamine 5-HT3 and 5-HT4 receptor subtypes, using functional as well as radioligand binding studies. The benzamide derivative cisapride was used as a comparison. In radioligand binding assays VB20B7 showed, like cisapride, a weak affinity at 5-HT3 receptors from rat cerebral cortex. The new compound lacked any affinity at other 5-HT receptors or at dopaminergic D2 receptors, whereas cisapride showed high affinity for the 5-HT4 receptors from guinea-pig hippocampus and moderate affinity at dopaminergic D2 receptors. In the non-stimulated guinea-pig ileum, the concentration-response curves to the specific 5-HT3 agonist 2-Me-5-HT and to 5-HT were shifted to the right by VB20B7. In the rat oesophagus tunica muscularis mucosae preparation (TMM), VB20B7 was evaluated for its activity at 5-HT4 receptors. VB20B7 behaved as a 5-HT4 receptor agonist, inducing a concentration-dependent relaxation of the preparation precontracted with carbachol. In this preparation, VB20B7 and cisapride were able to stimulate adenylate cyclase activity, an effect probably mediated through activation of 5-HT4 receptors, as can be inferred from the blockade by the 5-HT4 antagonist, tropisetron, of the enhanced cAMP formation. However, consistent with the lack of affinity at central 5-HT4 receptors, VB20B7 did not stimulate cAMP formation in guinea-pig hippocampal slices. VB20B7 also caused an increase in the twitch response of the transmurally stimulated guinea-pig ileum, although at a concentration higher than cisapride. This effect was blocked by desensitization of the 5-HT4 receptor with 5-MeOT and also by the 5-HT4 receptor antagonist tropisetron. Both VB20B7 and cisapride increased the K(+)-evoked acetylcholine release in this preparation. The results show that VB20B7 possesses affinity for 5-HT4 receptors located in the rat TMM and guinea-pig ileum preparations, but is devoid of affinity at central 5-HT4 receptors. In addition, VB20B7 shows low to moderate affinity at both central and peripheral (enteric) 5-HT3 receptors. The interaction of VB20B7 with the peripheral 5-HT4 and 5-HT3 receptors may be relevant for the gastrokinetic effects of the new compound.

Animals↗