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PubMed1990

The effect of isatin (tribulin) on metabolism of indoles in the rat brain and pineal: in vitro and in vivo studies.

Isatin (Tribulin) produced a dose-dependent inhibition of both MAO A and MAO B in broken cell preparations from rat brain and pineal. However, isatin administered in vivo (80-160 mg/kg) to the intact animal significantly increased brain, but not pineal, serotonin and did not affect 5HIAA or other indoles in either brain or pineal. Further, in vivo administration did not produce detectable MAO inhibition in either tissue. In pineal organ culture, addition of isatin up to 1mM had no influence on the concentrations of pineal indoles or the activities of monoamine oxidase or serotonin N-acetyltransferase. However, the diazepam augmentation of beta adrenergic induction of serotonin N-acetyltransferase activity was blocked by isatin. The results of these studies call into question the proposed role of isatin as an endogenous monoamine oxidase inhibitor but support a possible role as a benzodiazepine receptor blocker.

Animals↗
PubMed1992

Inhibitory potency of some isatin analogues on human monoamine oxidase A and B.

Isatin is an endogenous compound which acts as a selective inhibitor of monoamine oxidase (MAO) B. In this study a range of isatin analogues were tested for their in vitro inhibition of human MAO A and B. Most of the analogues were less potent than isatin. Hydroxylation of the aromatic ring changed the inhibitory potency in favour of MAO A, with 5-hydroxyisatin being a potent and selective MAO A inhibitor (IC50 8 microM). Isatinic acid, which is formed reversibly from isatin at alkaline pH, showed no inhibition.

Blood Platelets↗
PubMed2001

Cyclic GMP excretion blocked by isatin administration under conditions of fluid overload.

Isatin is a potent inhibitor of atrial natriuretic peptide (ANP) receptors and ANP-induced generation of cGMP in vitro. This study was designed to determine whether it had a similar effect in vivo, using a model of fluid overload known to induce ANP. We confirmed that this model increased urinary output of cGMP 3 hr after volume loading, and showed that this effect was blocked by i.p. injection of isatin (50 mg/kg). Isatin had no effect on urine volume or sodium output. However, isatin did have an effect on plasma protein concentration, both compared with control values, compatible with shifting fluid to the vascular compartment, and after volume overload, in which it normalised such a shift. Isatin thus affected both the generation of cGMP and fluid balance in vivo.

Analysis of Variance↗
PubMed2002

Effect of isatin on nitric oxide-stimulated soluble guanylate cyclase from human platelets.

Isatin, an endogenous indole, has previously been shown to inhibit atrial natriuretic peptide (ANP)-stimulated particulate guanylate cyclase activity. Here, it was shown that it can be transported to human platelets where it inhibited nitric oxide (NO)-stimulated soluble guanylate cyclase activity obtained from human platelets. The effect was most pronounced at 10(-8)M isatin and is the most potent effect of isatin yet observed. The dose response curve was bell shaped with higher doses becoming less effective. The maximal inhibition observed was of 40%. Isatin had no effect on protoporphyrin IX-stimulated guanylate cyclase. Isatin-dependent regulation of ligand-stimulated guanylate cyclases is suggested to promote a stress-induced switch in metabolism.

Blood Platelets↗
PubMed1999

Efficacy of isatin analogues as antagonists of rat brain and heart atrial natriuretic peptide receptors coupled to particulate guanylyl cyclase.

Isatin is an endogenous indole and an inhibitor of atrial natriuretic peptide (ANP) receptors coupled with particulate guanylyl cyclase (GC). In this study, several isatin analogues were tested as inhibitors of ANP-stimulated GC in rat brain and heart membranes. None of these analogues affected activity in the absence of ANP, or stimulated ANP-induced activity. In both tissues, some 5-substituted isatins (5-hydroxyisatin, 5-methylisatin, and 5-aminoisatin) exhibited more effective inhibitory activity than isatin itself, with IC50 values in the range 1.3-20 microM. The efficacy of other analogues varied and was not consistent between the two tissues, raising the possibility of receptor heterogeneity and relative selectivity of inhibition. Some substituted isatins may have a role as pharmacological tools for investigating the physiological roles of natriuretic peptides and their receptors.

Animals↗
PubMed2000

The action of isatin (2,3-dioxoindole) an endogenous indole on brain natriuretic and C-type natriuretic peptide-induced facilitation of memory consolidation in passive-avoidance learning in rats.

Isatin is an endogenous indole which has been shown to counteract some of the effects of atrial natriuretic peptide (ANP) both in vitro and in vivo. The present study was designed to determine whether it could antagonise in vivo effects of the related peptides brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The model used was consolidation of memory in a one-trial step-through passive-avoidance paradigm in the rat. Previous studies have shown that all three peptides (1 microg intracerebroventricular) can consolidate such learning and increase latency to entry a dark box. Isatin was given intraperitoneally at doses of 5, 10 and 50 mg/kg before the peptide, or a saline control. Both BNP and CNP significantly increased the latency of entry. Isatin alone had no effect. Isatin reduced the effect of both BNP and CNP; this was significant for its effect on BNP at 50 mg/kg and on CNP at both 10 and 50 mg/kg. These results show that isatin can inhibit behavioural effects of BNP and CNP as well as ANP.

Animals↗
PubMed2006

5-pyrrolidinylsulfonyl isatins as a potential tool for the molecular imaging of caspases in apoptosis.

Caspases are the unique enzymes responsible for the execution of the cell death program and may represent an exclusive target for the specific molecular imaging of apoptosis in vivo. 5-Pyrrolidinylsulfonyl isatins represent potent nonpeptidyl caspase inhibitors that may be suitable for the development of caspase binding radioligands (CBRs). (S)-5-[1-(2-Methoxymethylpyrrolidinyl)sulfonyl]isatin (7) served as a lead compound for modification of its N-1-position. Corresponding pairs of N-1-substituted 2-methoxymethyl- and 2-phenoxymethylpyrrolidinyl derivatives were examined in vitro by biochemical caspase inhibition assays. All target compounds possess high in vitro caspase inhibition potencies in the nanomolar to subnanomolar range for caspase-3 (Ki=0.2-56.1 nM). As shown for compound (S)-1-(4-(2-fluoroethoxy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (35), the class of N-1-substituted 5-pyrrolidinylsulfonyl isatins competitively inhibits caspase-3. All caspase inhibitors show selectivity for the effector caspases-3 and -7 in vitro. The 2-methoxymethylpyrrolidinyl versions of the isatins appear to possess superior caspase inhibition potencies in cellular apoptosis inhibition assays compared with the 2-phenoxymethylpyrrolidinyl inhibitors.

Apoptosis↗
PubMed2004

Superoxide converts indigo carmine to isatin sulfonic acid: implications for the hypothesis that neutrophils produce ozone.

Recently, it was proposed that neutrophils generate ozone (Wentworth, P. J., McDunn, J. E., Wentworth, A. D., Takeuchi, C., Nieva, J., Jones, T., Bautista, C., Ruedi, J. M., Gutierrez, A., Janda, K. D., Babior, B. M., Eschenmoser, A., and Lerner, R. A. (2002) Science 298, 2195-2199; Babior, B. M., Takeuchi, C., Ruedi, J., Gutierrez, A., and Wentworth, P. J. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 3031-3034). Evidence for the proposal was based largely on the chemistry of ozone reacting with indigo carmine to produce isatin sulfonic acid. In this investigation, we have examined the specificity of this reaction and whether it can be used as unequivocal evidence of ozone production by neutrophils. Stimulated neutrophils promoted the loss of indigo carmine and formation of isatin sulfonic acid in a reaction that was completely inhibited by superoxide dismutase. Methionine, which scavenges ozone, singlet oxygen, and hypochlorous acid, had no effect on the reaction. Neither did catalase or azide, which scavenge hydrogen peroxide and inhibit myeloperoxidase, respectively. From these results, it is apparent that superoxide was responsible for bleaching indigo carmine. Superoxide generated using xanthine oxidase and acetaldehyde also converted indigo carmine to isatin sulfonic acid in a reaction that was completely inhibited by superoxide dismutase and unaffected by catalase. When the xanthine oxidase reaction was carried out in H(2)(18)O, the proportion of (18)O incorporated into the isatin sulfonic acid was the same as that found for ozone. Thus, reactions of ozone and superoxide with indigo carmine are indistinguishable with respect to isatin sulfonic acid formation. We conclude that bleaching of indigo carmine cannot be used to invoke ozone production by neutrophils. Studies using indigo carmine to implicate ozone in other biological processes should also be interpreted with caution.

Chromatography, High Pressure Liquid↗
PubMed1975

Arenavirus inactivation on contact with N-substituted isatin beta-thiosemicarbazones and certain cations.

N-methyl and N-ethyl isatin beta-thiosemicarbazones inactivate cell-free Parana and Pichinde viruses as well as three strains of lymphocytic choriomeningitis virus. This antiviral activity is abolished in the presence of the chelating agent EDTA. The rate of virus inactivation by N-methyl isatin beta-thiosemicarbazone is greatly enhanced and controlled by the addition of cupric sulphate. Divalent cations of other first transition series metals are less effective. A difference exists in the copper requirement for fast inactivation of the prototype arenavirus (lymphocytic choriomeningitis) and the Tacaribe Complex of viruses (Parana and Pichinde). In the presence of 20 muM-N-methyl isatin beta-thiosemicarbazone, LCM and Pichinde viruses can be inactivated at about the same rate if 20 muM-CuSO4 is added to the former and 160 muM-CuSO4 is added to the latter. Using 20 muM-N-methyl isatin beta-semicarbazone and CuSO4 the inactivation of LCM is reduced, but not eliminated, in the presence of an equal amount of infectious Pichinde virus. Crude and highly purified Pichinde virus are inactivated at the same rate when exposed to identical concentrations of N-methyl isatin beta-thiosemicarbazone and cupric sulphate. There is little detectable change in the inactivation rates when Pichinde or LCM viruses are grown in a variety of different cell lines.

Cell Line↗
PubMed1960

The structure-activity relationships of the antiviral chemotherapeutic activity of isatin beta-thiosemicarbazone.

As part of an investigation devoted to the development of new antiviral agents a compound of established antiviral activity has been subjected to systematic structural modification. The structure-activity data so obtained have been used in the design of new compounds, some of which are described. The compound chosen was isatin beta-thiosemicarbazone, which has high activity against neurovaccinia infection in mice, and a 4-point parallel-line assay of in vivo chemotherapeutic activity has been developed, which has enabled the activity of the derivatives to be determined against isatin beta-thiosemicarbazone as a standard. The overall dimensions of the isatin beta-thiosemicarbazone molecule appear to be nearly maximal for the retention of high activity, as all substituents in the aromatic ring decrease the activity irrespective of their nature or position. The projection of the -CS.NH(2) group in relation to the ring nitrogen was found to be critical, as the alpha-thiosemicarbazone was inactive. A number of modifications of the side-chain were investigated:all led to reduction or loss of antiviral activity. The antiviral activity showed a positive correlation with chloroform solubility over a considerable range. The most active compound encountered was 1-ethylisatin beta-thiosemicarbazone, with an activity of 286 (isatin beta-thiosemicarbazone identical with100). Isatin beta-thiosemicarbazone showed no activity against 15 other viruses, and 20 related compounds showed on activity against ectromelia.

Animals↗
PubMedDate not supplied

[Interaction of pyruvate kinase with isatin and deprenyl].

The glycolytic enzyme, pyruvate kinase, exhibits moderate affinity [3H]isatin binding (KD approximately 10 microM), which is inhibited by ATP (IC50 25 microM) and deprenyl (IC50 5 microM). Interaction of pyruvate kinase with isatin and its inhibition by ATP and deprenyl has also been confirmed using an independent biosensor technique and immobilized isatin analogue, aminoisatin. This effect has some specificity because the enzyme, creatine phosphokinase, does not exhibit specific isatin-binding. It is suggested that interaction of pyruvate kinase with isatin may reflect some non-glycolytic functions of this enzyme.

Animals↗
PubMed1980

[Studies of the effect of 2,3-dioxoindolin (isatin) in comparison with serotonin on the isolated guinea pig ileum].

In preparations of the isolated guinea-pig ileum 2,3-dioxoindoline shows a dose-dependent stimulating activity. In a contraction range between 5 x 10(-5) to 2 x 10(-3) moles/l this compound is spasmogenic and causes concentration (pD2 = 3.3). Prolonged contact time of higher concentrations of isatin results in a reduction of excitation and a relaxation of the ileum. An additive synergism is seen in combined treatment with serotonin. Pretreatment with serotonin antagonists reduces the stimulating effect of isatin. Quantitative differences in inhibition by dihydroergotamine and benzyloxygramine in contrast to morphine or atropine actions provided evidence that the stimulating activity of isatin is mainly mediated through the "D" receptors on the smooth muscle cells. Besides its stimulating effect isatin also exhibits blocking activity when tested against 5-HT (ACh). In high concentration (> 2 mmoles/l) isatin is able to antagonize--after only 2 min of pre-incubation--responses to 5-HT completely. In this range dose-response curves become progressively flatter and their maxima decline in a non-competitive way.

Animals↗
PubMed1994

Studies on peripheral actions of isatin.

The possible peripheral actions of isatin were studied in vivo and in vitro preparations in different experimental models, using conventional techniques. The results showed spasmogenic responses of isatin on guinea pig, rat and rabbit ileum and fundus of rat stomach. Histamine induced broncho-constriction could be antagonised by isatin. Isatin had cardioinhibitory effect on isolated frog heart and had hypotensive and respiratory depressant activities in dog. Isatin had antidiuretic effect. It was devoid of any effect on inflammation and gastric activities. The present results suggest a possible involvement of heterogenic 5-HT3 receptors in gastrointestinal smooth muscle.

Animals↗
PubMed1994

Inhibition of rabbit intestinal brush border sucrase by indolin 2,3-dione (isatin) at pH 5.0.

Isatin (10 mM) inhibited the activity of rabbit brush border sucrase by 60% at pH 5.0 but it had no effect on enzyme activity around neutral pH. Isatin inhibition of sucrase was unaffected by Na+ ions but K+ and Cs+ ions reduced enzyme inhibition, partially. Kinetic analysis revealed that sucrase inhibition by isatin at acidic pH was non-competitive with Ki of the order 6.5-7.8 mM. Isatin together with 4 mM harmaline or iodoacetate (3 mM) or dithionitrobenzene (2 mM) yielded 80-85% inhibition of the enzyme. These observations suggest that inhibitory sites for isatin, harmaline and -SH group reacting agents are distinct in rabbit brush border sucrase.

Animals↗
PubMed1996

Isatin (2,3-dioxoindole): a competitive inhibitor of Na(+)-dependent lysine uptake in rat instestine.

Isatin (2,3-dioxoindole) competitively inhibited (27-40%) Na(+)-dependent L-lysine uptake in rat intestine. The value of Kt was increased from 3.04 mM in control to 5.88 mM in presence of 10 mM isatin. Effect of isatin on the Na(+)-independent amino acid uptake was insignificant (12-18%). The inhibitory constant (Ki) was 2.8 mM under these conditions. The observed inhibition was unaffected by -SH group reacting agents. Isatin (1-10 mM) inhibited Na+, K(+)-ATPase activity in intestine in vitro, the maximum inhibition (66%) being at 10 mM isatin concentration. But the drug had no effect on enzyme activity under in vivo conditions.

Animals↗
PubMedDate not supplied

[Isatin: possible role in functional interaction of natriuretic peptides and monoamines].

Isatin is an endogenous compound recently discovered in mammalian tissues and body fluids. It has a distinct distribution in rat brain, with a highest concentration, in the hippocampus, of 0.1 microgram/g. Its origin and metabolic pathways remain unclear. In vitro, isatin selectively inhibits monoamine oxidase (MAO) B (IC50 3-8 microM, Ki approximately 20 microM) and, more potently, atrial natriuretic peptide(ANP) binding (IC50, 0.4 microM). Convulsant doses of pentylene tetrazole result in increased isatin level in the brain. Small amounts of isatin are anxiogenic in rodent models, but higher doses cause sedation and possess anticonvulsant action. Isatin administration also increases monoamine levels in the brain and reduces daily urine output.

Animals↗
PubMed1966

Conversion of isatin to isatate as related to growth promotion in Avena coleoptile and pisum stem sections.

Isatin, (indole 2,3-dione), which promotes elongation of Pisum stem sections at concentrations exceeding 0.1 mm, promotes elongation of Avena coleoptile sections only at higher concentrations, exceeding 1 mm. Aged isatin solutions are more active than fresh solutions, due to the slow, spontaneous conversion to isatate (o-aminophenylglyoxylate). A concentration of 0.1 mm aged isatin is as active in Avena coleoptile sections as in peas. Isatate has been independently synthesized and its auxin activity in both Avena coleoptile and Pisum stem sections confirmed. The synthetic isatate is more effective than isatin in both systems. This suggests that the auxin activity of isatin is due to its conversion to isatate.

Journal Article↗
PubMed1994

Isatin as an auxin source favoring floral and vegetative shoot regeneration from calli produced by thin layer explants of tomato pedicel.

Thin layer explants taken from the pedicels and peduncles of flowering tomato plants yielded calli with great organogenetic potential. Of the 15 cultivars tested, 7 regenerated roots, shoots and eventually entire fruit-bearing plants. Calli grown on modified Murashige-Skoog medium responded to varied auxins and cytokinins with different morphogenetic patterns. Thus, naphthaleneacetic acid yielded root-producing calli, while the auxin precursor isatin (indole 2,3-dione) caused the production of calli with vegetative and floral shoots, rarely yielding roots. This may be related to isatin's slow, steady conversion to an active auxin (Plant Physiol 41:1485-1488, 1966) in contrast with naphthaleneacetic acid's immediate presentation of a high level of active auxin. The highest incidence of vegetative shoot (100%) and flower (50%) formation was obtained with 10 micromoles isatin and 3 micromoles zeatin. A few of the flowers developed into ripe fruits. The high frequency of induction of vegetative shoots and flowers before roots with isatin suggests its utility in micropropagation from plant tissue cultures.

Culture Media↗