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Biomedical subjects

A Monge

Publications and source records attributed to A Monge.

At least 55 records · Page 3Linked to original sources
PubMed1997

VB20B7, a novel 5-HT-ergic agent with gastrokinetic activity. II. Evaluation of the gastroprokinetic activity in rats and dogs.

The gastrokinetic activity of 2[1-(4-piperonyl)piperazinyl]benzothiazole (VB20B7), a new compound with 5-HT4 receptor agonist and weak 5-HT3 receptor antagonist properties has been studied in rats and dogs. The effects of VB20B7 were investigated in physiological conditions and in a model of gastroparesis induced by the alpha 2-adrenergic agonist UK-14304 and compared with cisapride. In rats, both VB20B7 and cisapride enhanced gastric emptying of indigestible solids (steel spheroids) and liquids (phenol red) at doses of 5-10 mg kg-1 by mouth. Gastric emptying of solid radiopaque markers in fasted beagle dogs was enhanced significantly by VB20B7 (0.25-1 mg kg-1 p.o.) whereas the effect of cisapride (0.5-2 mg kg-1 p.o.) did not reach statistical significance. Similar results were found when the radiopaque markers were given to the dogs following a standard solid meal. The delayed gastric emptying of indigestible solids and radiopaque markers by UK-14304 was reversed by oral administration of VB20B7 in both rats and dogs. Cisapride, however, was only effective in rats. In addition, gastric emptying of a digestible solid/liquid meal was assessed by quantitating the rate of appearance of the radioactive markers in the duodenum of dogs. VB20B7 (0.2-1 mg kg-1, i.v.) enhanced gastric emptying of both solid and liquid phases while cisapride only enhanced emptying of the solid phase. The present study indicates that acute oral and intravenous administration of VB20B7 accelerates gastric emptying of both solids and liquids in different animal models.

Animals↗
PubMed1997

Urodynamic and neurophysiological evaluation in Parkinson's disease and multiple system atrophy.

AIMS: To determine whether Parkinson's disease and multiple system atrophy each has a distinct pattern of micturition abnormalities and whether a urodynamic evaluation could be useful in the differential diagnosis between the two diseases. METHODS: Sixty two patients (30 with Parkinson's disease and 32 with multiple system atrophy) underwent a complete urodynamic evaluation and neurophysiological testing. RESULTS: Of the parkinsonian patients 36.6% had normal micturition findings with normal bladder sensitivity; 26.7% had delayed or incomplete pelvic floor relaxation; 26.7% had hyperreflexia with vesicosphincteric synergy; and 10% had hyperreflexia with vesicosphincteric synergy associated with incomplete pelvic floor relaxation. Parkinsonian patients with a normal urodynamic pattern had significantly less severe disease and a shorter duration of disease in years than those who had abnormal patterns. Patients with hyperreflexia had significantly higher severity of disease. All the patients with multiple system atrophy had hyperreflexia with synergy. Two urodynamic patterns were identified: hyperreflexia with vesicosphincteric synergy (90.6% of patients), and hyperreflexia with vesicosphincteric synergy and incomplete pelvic floor relaxation (in 9.4%). Hyperreflexia with synergy correlated neither with the severity nor with the duration of disease. Sphincter EMG analysis showed that all the parkinsonian patients had normal sphincter EMG whereas 24 of the 32 patients with multiple system atrophy had neurogenic signs. CONCLUSIONS: Urodynamic evaluation and sphincter EMG are both useful tests in the differential diagnosis between Parkinson's disease and multiple system atrophy. Urodynamic findings may be abnormal before patients with multiple system atrophy reach an advanced stage of the disease. Recordings of EMGs from perineal muscles become abnormal as the disease progresses in multiple system atrophy but not in Parkinson's disease.

Aged↗
PubMed1997

Structure-activity relationships in quinoline Reissert derivatives with HIV-1 reverse transcriptase inhibitory activity.

The relationship between the chemical structure and the HIV-1 RT inhibitory activity has been studied for a series of quinoline derivatives. Two methods were used: a standard QSAR analysis, by combining the methods of Hansch and Free-Wilson, and an analysis using quantum chemistry indices as descriptor parameters, by the semiempirical method AM1. The equations obtained lead to the proposal that the activity of the compounds increases, mainly, with the presence of electron-withdrawing substituents in position 6 of the quinoline ring that cause a decrease in the energy from the molecular orbital LUMO. In turn, this fact leads to the proposal that the most important interaction of these compounds with the HIV-1 RT is a charge transfer type interaction, with the quinoline aromatic ring acting as acceptor.

Anti-HIV Agents↗
PubMed1997

Synthesis and evaluation of new Reissert analogs as HIV-1 RT inhibitors. 2. Benzo[f]quinoline and pyridine derivatives.

The synthesis and preliminary evaluation of new benzo[f]quinoline and pyridine derivatives, obtained by application of the Reissert method and its modifications, as HIV-1 RT inhibitors and anti-infectives are presented. The most active products against HIV-1 RT wild type are the ethyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2b, propyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2c, and 2-cyano-1-(2'-furoyl)-1,2-dihydrobenzo[f]quinoline 2n, which maintain their activity against the mutant type P236L, resulting inactive against the Y181C type. Using the data previously obtained by our research team for analogous series derived from quinoline as reference, the compounds which have now been obtained present an increase in the cytotoxic character attributable to the introduction of a benzene ring fused with the quinoline base nucleus, as well as a decrease of the activity as HIV-1 RT inhibitors when the quinoline benzenic ring is eliminated.

Anti-HIV Agents↗
PubMed1997

Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives.

The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.

Anti-HIV Agents↗
PubMed1997

Physico-chemical properties and stability of the new hypoxia-selective agent 7-chloro-3-[[N,N-dimethylamino)propyl]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxide hydrochloride.

7-Chloro-3-[[N,N-dimethylamino)propyl]amino]-2-quinoxalinecarbonitril e 1,4-di-N-oxide hydrochloride (Q-85 HCl), a new hypoxia-selective agent, was studied to clarify its physico-chemical properties. Melting point, spectra (UV, IR, NMR, MS), thermal behaviour, solubility, pKa, partition coefficient and chromatographic characteristics (TLC, HPLC) have been determined. The stability of Q-85 HCl was studied under various conditions by HPLC. Q-85 HCl in solid state was very stable to heat and fairly stable to light. Some degradation products of Q-85 HCl were identified in basic solution.

Calorimetry, Differential Scanning↗
PubMed1997

Determination of a new hypoxia selective agent from 2-quinoxalinecarbonitrile 1,4-di-N-oxides in plasma by high performance liquid chromatography.

A high performance liquid chromatography (HPLC) method was developed and validated for the determination of 7-chloro-3-[[(N,N-dimethylamino)propyl]amino]-2-quinaxolinecarbonitri le 1,4-di-N-oxide (Q-85), a new hypoxia-selective agent, in plasma. The assay involves extraction into diethylether-dichloromethane (2:1) from plasma and subsequent analysis by reversed-phase HPLC with ultraviolet detection at 292 nm. Response was linear in the range of 0.4-20 micrograms/ml of plasma and the detection limit was 0.05 micrograms/ml. The extraction recovery was about 90%. The within and between day coefficients of variation did not exceed 6.1%. This HPLC assay has been applied to determine Q-85 in plasma samples taken during pharmacokinetic studies in mice.

Animals↗
PubMed1996

Synthesis and 5-HT3 affinity of new 3-substituted indoles at central nervous system.

A series of 3-imino and 3-aminomethyl-N-methylindoles, in which the amine substituents were 3-quinuclidyl and 1-adamantyl groups, were synthesized and their in vitro affinity towards 5-HT3 central receptors evaluated. Of the nine compounds tested, three caused displacement of 3H-BRL 43694 binding to 5-HT3. 2-Chloro-3-(3-quinuclidylimino)-1-methylindole, 4, was the most potent compound with an IC50 = 5.15 10(-8) M. Moreover, the monoamine oxidase inhibition activity was tested and three compounds were shown to be MAO inhibitors, their IC50 was in the range of that of (-)-Deprenyl. Again, 4 was the most potent compound. Structure-activity relationships within the series are briefly discussed.

Animals↗
PubMed1995

Hypoxia-selective agents derived from 2-quinoxalinecarbonitrile 1,4-di-N-oxides. 2.

Hypoxic cells are an important target for antitumor therapy because tumors are typically characterized by such cells. Virtually all tumors which are present as solid masses contain hypoxic cells, while normal cells generally have an adequate supply of oxygen. Accordingly, antitumor agents can be made selective for tumors by virtue of high activity under hypoxic conditions. The initial purpose of this work was to determine the influence of different groups in position 3. Thus, the synthesis of some 3-NH-substituted derivatives (2a, 3a, 4a) starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide (1a) is described. Reductive deamination of compounds 1a-k provides the 2-quinoxalinecarbonitriles 5a-k, which are more potent, while selectivity is maintained or increased in some derivatives. The compound 7-(4-nitrophenyl)-2-quinoxalinecarbonitrile 1,4-di-N-oxide (5k) is 150-fold more potent than tirapazamine (3-amino-1,2,4- benzotriazine 1,4-di-N-oxide), which has been used as a standard. Three derivatives (5g,i,k) show a hypoxic cytotoxicity ratio (HCR) > or = 200, better than that of tirapazamine (HCR = 75) in V79 cells. Replacement of the 3-amino group by chlorine affords the potent but nonselective 3-chloro derivatives 6a-k showing similar toxicities under both aerobic and hypoxic conditions. These compounds were used as intermediates for the synthesis of a new series of water-soluble compounds derived from 3-[[(N,N- dialkylamino)alkyl[amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxides 10a-i and 11a-i. The 7-chloro and the 7-trifluoromethyl derivatives 10b,f have demonstrated high potency (0.4 and 0.3 microM) and excellent selectivity (HCR = 250 and 340). Several 7-chloro analogues, 12b, 13b.1,b.2, and 14b, and the dimer 16b have been prepared and evaluated in order to determine the optimum lateral chain in position 3, which appears to be the [(N,N-dimethylamino)propyl]amino moiety.

Animals↗
PubMed1995

Hypoxia-selective agents derived from quinoxaline 1,4-di-N-oxides.

Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substitutents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V). The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 63, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.

Animals↗
PubMed1995

Computer modeling of protein folding: conformational and energetic analysis of reduced and detailed protein models.

Recently we developed methods to generate low-resolution protein tertiary structures using a reduced model of the protein where secondary structure is specified and a simple potential based on a statistical analysis of the Protein Data Bank is employed. Here we present the results of an extensive analysis of a large number of detailed, all-atom structures generated from these reduced model structures. Following side-chain addition, minimization and simulated annealing simulations are carried out with a molecular mechanics potential including an approximate continuum solvent treatment. By combining reduced model simulations with molecular modeling calculations we generate energetically competitive, plausible misfolded structures which provide a more significant test of the potential function than current misfolded models based on superimposing the native sequence on the folded structures of completely different proteins. The various contributions to the total energy and their interdependence are analyzed in detail for many conformations of three proteins (myoglobin, the C-terminal fragment of the L7/L12 ribosomal protein, and the N-terminal domain of phage 434 repressor). Our analysis indicates that the all-atom potential performs reasonably well in distinguishing the native structure. It also reveals inadequacies in the reduced model potential, which suggests how this potential can be improved to yield greater accuracy. Preliminary results with an improved potential are presented.

Algorithms↗
PubMed1995

New indole and pyridazinoindole analogs--synthesis and study as inhibitors of phosphodiesterases and as inhibitors of blood platelet aggregation.

This paper presents the synthesis of new indole, pyridazino[4,5-b]-indole, and pyridazino[4,5-a]indole analogs as well as a study of their "in vitro" activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro-aggregants, is also included. The selected compounds 8-benzyloxy-3,4-dihydro-1-(3,4,5-trimethoxy)benzylideneaminopyridazin o[4,5- b]indole 14g, and 8-benzyloxy-4-[(3,4-dimethyl)pyrazolyl]pyridazino[4,5-b]indo le 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8-benzyloxy-3,4-dihydro-1-[4-(methyl)piperazino]acetamidopyrida zino[4,5- b]indol-4-one 16c and 8-benzyloxy-3,4-dihydro-1-[4-(2- methoxyphenyl)piperazino]acetamidopyridazino[4,5-b]indol-4-o ne 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.

Animals↗
PubMed1995

The pharmacology of VA21B7: an atypical 5-HT3 receptor antagonist with anxiolytic-like properties in animal models.

VA21B7 (3-[2-(4'-piperonylpiperazinyl) indolyl] carboxaldehyde) was synthesized as a potential 5-HT3 receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT3 receptors as compared to other receptors studied, it was not a potent 5-HT3 receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remarkable anxiolytic-like effect was found at doses of 2-500 micrograms/kg IP and also at low oral doses, in the microgram range. These drug doses did not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished-drinking. VA21B7 was compared with standard 5-HT3 receptor antagonists such as ondansetron, tropisetron and granisetron, with the 5-HT1A agent buspirone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25-0.5 mg/kg IP or 2-4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drinking test. The dose-response curve was bell-shaped with a peak at 2-4 mg/kg. At variance with other studies, 5-HT3 receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic action in the light/dark test was not flumazenil-sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for 15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2-4 mg/kg reduced the memory deficits induced in rats by scopolamine. Much higher doses were necessary to decrease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential interest as an anxiolytic in humans.

Analgesics↗
PubMed1995

Inotropic and chronotropic effects of 4-(4'-n-butylaniline)-7,8- dimethoxy-5H-pyrimido[5,4-b]indole in guinea-pig atria.

Cardiotonic effect of 4-(4'-n-butylaniline)-7,8-dimethoxy- 5H-pyrimido[5,4-b]indole (B11) was investigated in isolated cardiac tissue preparations. The action of this agent on force of contraction, beating frequency and cyclic nucleotide phosphodiesterase (PDE) activity was studied. Amrinone was used for comparison. B11 produced concentration-dependent (5 x 10(6)-1 x 10(-4)M) positive inotropic and positive chronotropic responses in guinea-pig atrial tissues. The potency of B11 was greater than that of amrinone. The cardiotonic effects of B11 were not modified by beta-adrenoceptor blockade. Carbachol inhibited the positive inotropic effect of B11. The activity of B11 was increased in desensitized left atrial tissues. B11 inhibited the activities of PDE isoenzymes (type I, II, IV and V) from dog heart ventricle and PDE type IV from guinea-pig heart ventricle nonselectively. It is concluded that B11 possesses potent positive inotropic activity in guinea-pig atria, and the effect is probably mediated by a non-selective inhibition of PDE activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one derivatives as diuretics.

A series of new 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e] pyrimidin-5-ones 3-substituted and/or 8,9-hydrogenated was prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. Diuretic and saliuretic activities were strongly influenced by substituents in 3-position. Quantitative structure-activity relationships show that electron withdrawn substituents in 3-position enhance both diuretic and saliuretic activities at 25 mg/kg. Global analysis of the variations introduced on pyridine, pyrimidine and thiazole rings of this tricyclic system showed an increases of diuretic and natriuretic activities when the formal charge on N9a and C9b increases. Potassium ion excretion also increases, although not as drastically a in the earlier cases. Regression equations were calculated by partial least squares method (PLS) and validated by the cross-validation (leave-one-out) technique.

Animals↗
PubMed1994

An algorithm to generate low-resolution protein tertiary structures from knowledge of secondary structure.

An algorithm is described to assemble the three-dimensional fold of a protein starting from its secondary structure. A reduced representation of the polypeptide chain is used together with a crude potential based on pair hydrophobicities. The method is shown to be successful in locating the native topology for two 4-alpha-helix bundles, myohemerythrin and cytochrome b-562.

Algorithms↗