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Biomedical subjects

A Monge

Publications and source records attributed to A Monge.

At least 73 records · Page 4Linked to original sources
PubMed1994

Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.

New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.

Animals↗
PubMed1994

Clastogenicity of triazinoindole derivatives in relation with the physicochemical properties of the substituents.

The clastogenicity of four compounds of the series 3-(4'-substituted-benzylidenamino)5H-1,2,3-triazin [5,4-b]indol-4-one, which showed an important activity as inhibitors of platelet aggregation, has been evaluated. The compounds studied differed in the physicochemical properties of the substituent occupying the 4' position of the benzilidenamino group. The 4' substituents were: -H, -NO2, -OCH3 and -C6H5. They were tested on V-79 cells, both with and without metabolic activation, and structural chromosome aberrations were scored. Compounds with -H, -NO2 and -OCH3 radicals were active both with and without metabolic activation. Compound with -C6H5 radical was clastogenic only at the highest dose tested and with metabolic activation. It appears that the compound with the biggest and most hydrophobic substituent is the least clastogenic of the series. These results are in agreement with some previous ones obtained in bacteria and show a good correlation between the results of the Ames test and the structural chromosome aberrations test.

Bacteria↗
PubMed1994

Evaluation of the mutagenicity of 1-hydrazino-4-(3,5-dimethyl-1-pyrazolyl) pyridazino[4,5-b]indole.

The mutagenic potential of 1-hydrazino-4-(3,5-dimethyl-1-pyrazolyl) pyridazino [4,5-b]indole(A80a, CAS 135561-93-2), a new antihypertensive agent, was investigated in 3 test systems, according to the current EC Guidelines: Ames test with strains TA1535, TA1537, TA98 and TA100, SCE (sister chromatid exchange) test in V79 cells and micronucleus test in Swiss mice. No indications for a mutagenic potential were detected in bacteria and mice; positive results were obtained in eukaryotic cells. The potential for inducing chromosome aberrations in eukaryotic cells will be studied.

Animals↗
PubMed1993

Novel antagonists of 5-HT3 receptors. Synthesis and biological evaluation of piperazinylquinoxaline derivatives.

A series of piperazinylquinoxalines has been synthesized and studied as 5-HT3 receptor antagonists in different preparations. Antagonism to 5-HT in the longitudinal muscle of the guinea pig ileum was particularly prominent in cyanoquinoxaline derivatives with an alkyl substitutuent on the piperazine moiety. The pA2 of some selected compounds against the 5-HT3 agonist 2-methyl-5HT in the guinea pig ileum was in the range of tropisetron or ondansetron, and one of them, 7e, was more potent than these reference compounds by approximately 2 or 3 orders of magnitude. However, these compounds were markedly less potent than either tropisetron or ondansetron as displacers of 3H-BRL 43694 binding to rat cortical membranes or as antagonists of the Bezold-Jarisch reflex in rats. Piperazinylcyanoquinoxalines represent a new class of 5-HT3 antagonists with a selective effect on guinea pig peripheral receptors.

Animals↗
PubMed1993

New 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives: synthesis and studies as inhibitors of phosphodiesterases.

A series of 4-amino-7,8-dimethoxy-5H-pyrimido[5,4-b]indole derivatives has been synthesized. These compounds resemble carbazeram and other pyridazino compounds with activity in the cardiovascular system. Some of these new compounds possess inotropic activity (Table 2), with a complementary effect on the inhibition of different CGI-PDE (Table 3). The most active compounds 5, 6d, and 7 also possess activity as vasodilators (Table 4). Some of these new compounds inhibit blood platelet aggregation induced by ADP and AA and are active as inhibitors of human platelet PDEs (Tables 5 and 6).

Animals↗
PubMed1993

A novel class of cardiotonic agents: synthesis and biological evaluation of pyridazino[4,5-b]indoles with cyclic AMP phosphodiesterases inhibiting properties.

Some fused pyridazino[4,5-b]indoles (7) were synthesized. These new compounds present a planar topography and some resemblance to carbazeram, imadozan, and other pyridazino agents with cardiotonic activity. These compounds also possess a complementary effect as inhibitors of platelet aggregation. 6-(3,5-Dimethylpyrazolyl)-1,2,4-triazolo[4,3-b]pyridazino[4, 5-b]indole (7a) has a good profile as an inodilatador with antiaggregate activity due to the inhibition of phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Pharmacological characterization of the vasodilator effect of DF-100, a new pyridazino[4,5-b]indole, in vascular smooth muscle.

DF-100, i.e., 1-hydrazino-4-(3,5-dimethyl-1-pyrazolyl)-5H-pyridazino[4,5-b ]indole is a new pyridazino[4,5-b]indole derivative related to dihydralazine. The inhibitory effects of DF-100 were investigated on the contractions in isolated aorta and portal vein. In rat aorta, DF-100 inhibited both K(+)-induced as well as norepinephrine-induced contractions. DF-100 also caused dose-dependent relaxation of contractions produced by 80 mM K+. Moreover, DF-100 significantly inhibited the CaCl2 dose response in high-K+ depolarizing medium. DF-100 inhibited the phasic contractile response to norepinephrine and the caffeine-induced response, suggesting that this molecule affects the mobilization of Ca2+ from a membrane-bound pool. In rat portal vein, DF-100 inhibited the spontaneous rhythmic contractions. The results obtained in this study in isolated rat aorta and portal vein suggest that DF-100 has a direct vasodilating effect that could be attributed to inhibition of cellular Ca2+ influx and release from intracellular stores.

Animals↗
PubMed1993

New 2-aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-4-one derivatives as diuretics.

2-Aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-4-one derivatives having various substituents at the 4'-position, H or methyl at 1,3-positions and nitro or amino at 6-position were prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. 2-(3-Pyridyl) derivatives were inactive. 1,3-Dimethyl-6-nitro-2-phenyl derivatives (1) were active depending on the electronic character of the 4'-substituent but at the same time were sodium-sparing. However, 1(H),3(H)-6-nitro-2-phenyl derivatives (2) were generally inactive as diuretics but active as potassium-sparing drugs. 6-Amino-1(H),3(H)-2-phenyl derivatives (4) were active as diuretics depending on dipolar moment of the substituent at the 4'-position, and induced moderate potassium release. The 6-amino-2-(4-trifluoromethylphenyl)-1, 2,3,4-tetrahydropyrido [2,3-d]pyrimidin-4-one (4f) remained active up to a dosage of 3 mg/kg. The structure-activity relationships were carried out in light of the adaptative least squares (ALS) method and discriminant functions for diuretic compounds were established.

Animals↗
PubMed1993

New pyridazino[4,5-b]indole derivatives with inodilator and antiaggregatory activities.

Some 4-(3,5-dimethylpyrazol) 5H-pyridazino [4,5-b]indoles (7), 1,2,4-triazolo [4,3-b]pyridazino [4,5-b]indoles (9) and 1,2,4-tetrazolo [4,5-b]pyridazino [4,5-b] indoles (11) substituted in position 1 by amino groups have been synthesized and tested as inotropic agents and inhibitors of platelet aggregation. 6-Imidazolyl-11H-1,2,4-triazolo [4,3-b]pyridazino [4,5-b]indole (9) shows an activity superior to that of amrinone, with a notable selectivity towards phosphodiesterase (PDE) IV and PDEV, vasodilator activity and a good effect on blood platelet aggregation.

Animals↗
PubMed1992

Antihypertensive and vasodilator effect of A-80b, a new pyridazino indole derivative.

The hypotensive and antihypertensive activities of a A-80b, a newly synthesized pyridazino[4,5-b]indole derivate were investigated in anaesthetized rats. In vitro studies were also done to examine the possible mechanism of its vasodilator action. A 80b (3-15 mg/kg i.p.) showed potent and long-lasting antihypertensive activity in spontaneous hypertensive rats. In normotensive rats, A-80b (7.5-30 mg/kg i.p.) also lowered blood pressure but less than in hypertensive rats. The decrease in diastolic pressure was greater than the decrease in systolic pressure and cardiac frequency was not modified significantly. Contractile responses induced in isolated rat thoracic aorta by K+ and noradrenaline were inhibited by A-80b. In K(+)-depolarized rat aorta, A-80b showed dose-dependent inhibition of the Ca(2+)-induced contraction. Also, A-80b inhibited spontaneous contractions of rat portal vein. The vasodilator action seemed to be endothelium-independent. These results suggest that A-80b is a new chemical entity which exerts a hypotensive and antihypertensive effect, possibly attributable to vasodilator activity via interference with Ca2+ influx and probably Ca2+ mobilization from intracellular stores.

Animals↗
PubMed1992

New indole and triazino[5,4-b]indol-4-one derivatives: synthesis and studies as inotropics and inhibitors of blood platelet aggregation.

New triazino[5,4-b]indol-4-one derivatives carrying amino groups in position 3 were synthetized and tested as inotropic agents and inhibitors of platelet aggregation. 2h, 2p, 5p, and 6g are the most active as inotropic agents. Compounds were tested as inhibitors of platelet aggregation induced by adenosine 5'-diphosphate (ADP) and arachidonic acid (AA) (guinea pig whole blood). 2k, 2p, 5o, 6d, 6m, and 6o are the most active as inhibitors of the platelet aggregation induced by AA. 6d, 6h, and 6o are most active compounds also in the aggregation induced by ADP. Radioimmunoassay studies, following AA induced aggregation, measuring thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were carried out on compounds 2b, 2d, 2f, 2g, 2h, 2i, 2k, 2m, 2o, 2p, 2r, 5i, 5j, 5k, 5r, and 5f, which inhibit platelet aggregation induced by AA. None of the compounds tested turned out to be selective inhibitors. Compounds 2h and 2p showed both inotropic and platelet aggregation inhibiting activity.

Animals↗
PubMed1992

Quantitative structure-mutagenic activity relationships of triazino indole derivatives.

The mutagenicity of 3-(4'-benzylidenamino)-5H-1,2,3-triazin[5,4-b]-indol-4-one derivatives, new compounds with considerable platelet antiaggregating activity, was assayed with the Ames test using the Salmonella typhimurium strains TA97, TA98, TA100 and TA102. The adaptive least-squares method (ALS method) was used to carry out a quantitative structure-activity relationship (QSAR) analysis. Three equations, based on 10 congeners, were found for strains TA97, TA98 and TA100. The results suggest that lipophilicity of the substituent decreases the mutagenicity of the series.

Carcinogenicity Tests↗
PubMed1992

Bacterial mutagenic evaluation of a series of 4' substituted derivatives of 3-benzylidenamino-5H-1,2,3-triazin[5,4b]indol-4-one.

The mutagenicity of ten triazinoindole derivatives was studied in bacteria. The compounds form part of a 3-(4'-substituted-benzylidenamino)-5H-1,2,3-triazin[5,4-b]in dol-4-one series and differ in the physicochemical properties of the substituent at the 4' position of the benzylidenamino group: -H, -OH, -COOH, -OCH3, -COOCH3, -NHCOCH3, -C1, -NO2, -C6H5, and -OC6H5. They were tested in the TA97, TA98, TA100, and TA102 strains of Salmonella typhimurium, both with and without metabolic activation, using the preincubation procedure. Only the derivatives with phenyl and phenoxy substituents were non-mutagenic. The remaining compounds significantly increased the number of His+ revertants and showed three patterns of activity based upon their mutagenic potency and their response to metabolic activation. Size and hydrophobicity of the 4'-substituents are the physicochemical characteristics that most differentiate the mutagenic triazinoindole derivatives from the nonmutagenic ones.

Frameshift Mutation↗
PubMed1992

Detection of nephrotoxicity in cyclosporine-A amyotrophic lateral sclerosis patients by means of urinary cytology.

Exfoliative urinary cytology was used for two amyotrophic lateral sclerosis patients treated with 3 mg/kg/day cyclosporine (CsA) therapy in order to detect the onset of the nephrotoxic side-effects of the drug before the apparent deterioration of the patients' clinical condition. Of the two patients, only one showed clear morphological features of drug-related damage in a one year course of cyclosporine therapy, but these followed the increase in the serum kidney and liver laboratory parameters and did not prove useful for the early detection of nephrotoxicity. However, in this patient the renal damage was hallmarked by an increasing number of tubular cells or clusters of ill-defined renal cells in the urinary specimen, suggesting an ongoing tubular injury. The slight cytological alterations may possibly be due to the low CsA dosage used for these patients. The significance of these observations is tempered by the limited number of patients and specimens studied to date and further studies in nontransplanted patients are therefore advocated, particularly when higher CsA doses are employed.

Amyotrophic Lateral Sclerosis↗
PubMed1991

New 5H-pyridazino[4,5-b]indole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation and inotropics.

Some fused 5H-pyridazino[4,5-b]indoles (7-10), substituted in positions 1 and 4 by hydrazine and/or amino groups, have been synthesized. These new compounds present a planar topography, a dipole with an adjacent acidic proton, and a basic hydrogen-acceptor site opposite the dipole. These compounds have some resemblance to carbazeram and other pyridazino agents with cardiotonic activity. Some of the new compounds here described possess inotropic activity (Table I and II), with a complementary effect as inhibitors of platelet aggregation (Table III and IV). 1-Hydrazino-4-(3,5-dimethyl)-1-pyrazolyl-5H-pyridazino[4,5-b ]indole hydrochloride (7a.HCl) is the first compound described in the literature with activities as inhibitor of PDE-IV and as selective inhibitor of TXA2 synthetase (Table V).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Mutagenic evaluation of some triazino indoles using the Salmonella/mammalian microsome assay.

The mutagenicity of ethyl 1,2,3-triazino[5,4-b]indole-4-carboxylate N(3)-oxide (D3) and 2-chloroethyl 1,2,3-triazino-[5,4-b]indole-4-carboxylate N(3)-oxide (D4), heads of series of new products with considerable platelet antiaggregating and hypotensive activity, and their precursors 2-ethoxy-carbonylmethyl-1-methylindole-3-carboxylic acid (A3) and 2-(2-chloroethoxycarbonylmethyl)-1-methylindole-3-carboxylic acid (A4) were tested in four strains of Salmonella typhimurium (TA98, TA100, TA97 and TA102) using the standard plate incorporation technique. A3 and A4 were not mutagenic whereas D3 was mutagenic to all the strains and D4 was mutagenic to TA97, TA98 and TA100. The addition of 4 or 10% of S9 mix decreased the mutagenic activity of both compounds. This effect was independent of the concentration of S9 in the S9 mix.

Animals↗