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Seven solvent systems for the thin-layer chromatographic separation of hydrazidic monoamine oxidase inhibitor drugs have been developed. Detection of compounds at the microgram level was performed with the aid of thirteen spray reagents.
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Tuberculosis is one of the most common infectious diseases known to man. About 37% of the world's population (about 1.86 billion people) are infected with Mycobacterium tuberculosis. According to the World Health Organization, every year approximately 8 million people develop active tuberculosis and almost 2 million of those die from the disease. The incidence of multidrug-resistant tuberculosis (MDR-TB) is increasing. The present drug regimen for treating tuberculosis has been in existence for 30 years. New drugs that will shorten total treatment duration, improve the treatment of MDR-TB, and address latent tuberculosis are the most urgent need of tuberculosis control programs. A new series of synthetic 3-amino-4-arylpyridazino[4,3-b]indoles (pyridazinoindoles) were identified as inhibitors of Mycobacterium tuberculosis. The design, synthesis, and antimycobacterial activity of these compounds are described. While the most active compounds are still not comparable to the front-line drugs rifampicin and isoniazid, they do show promise. Most of the pyridazinoindoles with appreciable antituberculosis activity also inhibit monoamine oxidase, suggestive of a novel inhibitory effect on mycobacterial redox reactions.
Effect of monoamine oxidase inhibitor (MAOI) on the induction of persistent estrus by testosterone propionate (TP) was studied in Wistar strain female rats. Daily treatment with MAOI for the 1st 10 days of life accelerated the occurrence of persistent estrus in rats given TP at 8 days of age. The onset of persistent estrus occurred at 57.3+/2.0 days of age in these animals compared to 92.6+/5.5 days in saline-treated controls. The contribution of hypothalamic monoamines to the induction of persistent estrus by TP treatment in neonatal rats will be discussed.
In young Rats made hypothyroid from birth, the activity of monoamine oxidase at 20 days is smaller than controls in brain, heart and kidney. In Rats made hyperthyroid by injections of thyroxine, the activity is lower in brain kidney and liver and is 3.8 times higher in the heart.
The activity of monamine oxidase, an enzyme located almost exclusively at the outer mitochondrial membrane, toward the substrate phenylethylamine is used to report the oxygen pressure at the outer mitochondrial membrane of intact cardiac myocytes isolated from hearts of adult rats. The rate of substrate oxidation, under the conditions used, follows the Michaelis-Menten relation, and accordingly can be used as a measure of the local chemical activity of dissolved oxygen. The oxygen pressure at the outer mitochondrial membrane of myocytes, at rest and after 2- to 3-fold stimulation of respiratory oxygen consumption, differs from the extracellular oxygen pressure by at most 2 torr. This implies that most of the large, about 20 torr, difference in oxygen pressure between capillary lumen and mitochondria of the working heart must be extracellular. At physiologically relevant concentrations of the substrates phenylethylamine and norepinephrine, monoamine oxidase activity is relatively insensitive to extracellular oxygen pressure in the range 155 to 8 torr, suggesting a limited role for regulation of biogenic amine oxidation by oxygen availability.
Following thyroidectomy, monoamine oxidase (MAO) activities toward tyramine decreased significantly by 20% in the nucleus periventricularis and the nucleus arcuatus among the 3 hypothalamic nuclei of the rat, while MAO activity toward serotonin decreased significantly by 10% only in the nucleus periventricularis. It is suggested that thyroidectomy induced selective changes on the multiple forms of MAO in the discrete circumventricular nuclei.
These experiments show that in the rat corpus striatum the highest concentrations of p- and m-tyramine were found in the caudate nucleus while somewhat lower values were observed in the putamen and globus pallidus. Inhibition of monoamine oxidase by pargyline produced an increase in the concentration of both tyramines in the three areas. The effect of pargyline is more marked with p-tyramine, however, the regional distribution of both p- and m-tyramine are preserved after monoamine oxidase inhibition. In addition, the pargyline treatment produced a significant reduction in corpus striatum p-tyrosine while no changes were observed in the tryptophan concentrations.
A double-blind, cross-over trial with 12 patients with Alzheimer's disease (AD) was carried out primarily to test the suitability of this design in the investigation of the clinical effects of selegiline (10 mg/day) in AD. Cerebrospinal fluid (CSF) samples for the determination of concentrations of noradrenaline (NA) and several monoamine metabolites were collected at baseline and at the end of both four-week treatment periods (placebo and selegiline). The severity of dementia was assessed using Ferm's and Gottfries-Bråne-Steen (GBS) dementia scales. The concentrations of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the NA metabolites, 3,4-dihydroxyphenylglycol (DHPG), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) decreased significantly during selegiline treatment. There was a clear trend of reduction in concentrations of homovanillic acid (HVA) during selegiline treatment, whereas the concentrations of NA, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan did not differ significantly. The study design was not suitable for the analysis of the clinical results as there was a significant carry-over effect in both scales. As only the first period data could be used in the analysis, there were no significant differences in the scores of Ferm's or GBS scales, but clear positive trends could be detected in favour of selegiline.
A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.
Slices of caudate nucleus from pigmented and from albino rabbits were preincubated in vitro for 24 h with different concentrations of the neurotoxic compound MPP+. Subsequently, endogenous dopamine (DA) in the slices was determined by HPLC. MPP+ (1 and 3.2 mumol/l) was more effective in diminishing DA levels in caudate nucleus slices from albino than in slices from pigmented rabbits. Following 24 h pretreatment with MPP+, the accumulation of [3H]-DA in caudate nucleus slices from pigmented rabbits was either enhanced (at 0.32 mumol/l, 1 mumol/l and 3.2 mumol/l MPP+) or reduced (at 32 mumol/l MPP+). In contrast, MPP+ did not enhance the accumulation of [3H]-DA in caudate nucleus tissue from albino rabbits and was more potent in reducing the [3H]-DA content in slices from albino than in slices from pigmented rabbits. When the selective type A monoamine oxidase (MAO) inhibitor clorgyline was present during pre-incubation, but not when the selective type B MAO inhibitor deprenyl was, the concentration-response curve for MPP+ with caudate nucleus slices from pigmented rabbits was similar to that obtained with slices from albino rabbits. Clorgyline and deprenyl did not change the effects of MPP+ in caudate nucleus slices from albino rabbits. These findings are compatible with the hypothesis that the MAO within dopaminergic terminals in the caudate nucleus of pigmented, but not of albino, rabbits is of type A since MAO-A is preferentially inhibited by MPP+. In line with this hypothesis, the accumulation of the preferential MAO-A substrate [3H]-5-HT in caudate nucleus slices from pigmented rabbits was about 39% lower than that in slices from albino rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
The kinetics of platelet monoamine oxidase (MAO) were studied in 100 psychotic and manic patients and 36 controls. No relationship was found between MAO activity and response to lithium in the schizophrenic-like illnesses. However, the data do suggest there is an association between enzyme affinity (Km) and specific symptom clusters. Patients with the low Km variant of platelet MAO are enriched in depressive symptoms, while those with the high Km variant are enriched in manic symptoms.
An increase in platelet monoamine oxidase (MAO) B activity in drug-free parkinsonians (n = 6) compared with healthy controls (n = 10) has been confirmed using both phenylethylamine (PEA) and dopamine as substrates, reaching statistical significance in the case of PEA oxidising activity (p < 0.05). Thus, certain reports of raised platelet MAO B activity towards PEA but decreased activity towards dopamine in parkinsonians, raising the possibility of the existence of an abnormal form of MAO B in this condition, cannot be supported.
The denaturating effects of urea on clorgyline-produced inhibition of serotonin and tyramine deamination and deprenyl-produced inhibition of beta-phenylethylamine and tyramine oxidation were studied. It was shown that after preincubation of mitochondria with 1 and 2 M urea the intensity of inhibition by clorgyline and deprenyl of oxidation of these amines was not changed. With urea concentration of 3 and 4 M the inhibitory effect of clorgyline on deamination of serotonin and tyramine was increased, while that of deprenyl on oxidation of beta-phenylethylamine and tyramine was decreased. As a result of mitochondria treatment with 3 and 4 M urea the selectivity in inhibition by clorgyline of serotonin and tyramine deamination typical for intact mitochondria was reduced in the case of 3 M urea and eliminated in the case of 4 M urea. In intact mitochondria the intensity of inhibition by clorgyline of tyramine deamination in the presence of benzyl alcohol (competitive reversible MAO inhibitor) was increased, but the additive effect was not achieved. However, after preincubation of mitochondria with 3 M urea the summation of the inhibitory effects of clorgyline and benzyl alcohol was observed. The data obtained provide further evidence for the important role of spatial configuration of the monoamine oxidase molecule; the data are discussed in terms of arrangement on the protein molecule surface of the essential groups involved in the binding and deamination of amines for the inhibitory effects of clorgyline and deprenyl.
The extraction and partial purification of endogenous "monoamine oxidase (MAO) inhibitor-like" material from the monkey brain are described. The endogenous material (F-1 and F-2) obtained after Bio-Gel P-2 gel filtration and silica column chromatography inhibited MAO in the monkey brain mitochondria toward 5-hydroxytryptamine (5-HT), beta-phenylethylamine (beta-PEA), tyramine and dopamine as substrates. The inhibitory effects of F-1 and F-2 were non-linear concentration dependent, and F-1 non-competitively inhibited A-form MAO, while F-2 inhibited A-form MAO competitively and inhibited B-form MAO non-competitively. These substances were more potent inhibitors of A-form than of B-form MAO. F-2 was heat stable but liable to the treatment with pepsin and trypsin. F-1 was not inactivated by heat treatment and digestion with pepsin and trypsin. F-1 may be a low molecular weight (less than 1350) compound, including certain monoamines or their metabolites or other unidentified compounds, while F-2 was a low molecular weight (about 2500) peptide.
Serotonin, a preferred monoamine oxidase (MAO) A substrate may be deficient centrally in suicide victims. In postmortem samples of frontal cortex from suicide victims we demonstrated receptor changes in the serotonergic system supportive of this hypothesis. These changes were not accompanied in this series of brain samples by alterations in either MAO A or B enzyme kinetics. Thus brain MAO A is not a useful indicator of altered serotonergic function in suicide victims. We did confirm an age-related increase in cortical MAO B but not MAO A enzyme concentrations in both controls and suicide victims.
The lipophilicity (RM value) of seventeen monoamine oxidase inhibitory drugs was determined by reversed-phase thin-layer chromatography, and the effect of salt concentration on the reversed-phase retention was studied by adding ammonium chloride to the eluent. Each drug exhibited regular retention behaviour, its RM value linearly decreasing with increasing concentration of methanol in the eluent. Ammonium chloride decreased the retention: the effect was higher at lower salt concentrations, which indicates that the phenomenon is of saturation character. The influence of ammonium chloride depended on the concentration of methanol (on the dielectric constant of the eluent) suggesting that methanol suppresses the dissociation of ammonium chloride resulting in a modified salting-in effect.
A significant negative correlation between platelet monoamine oxidase (MAO) activity, a stable peripheral enzyme measure under genetic control, and sensation seeking, as measured using the Zuckerman Sensation Seeking Scale (SSS), has been reported for male subjects in several studies. As tobacco smoking has been related to both these measures, in the present study correlations were calculated among smoking and non-smoking male university students. Platelet MAO activity was negatively correlated with the Disinhibition and Total scales of the SSS. These correlations were not significantly different in smokers and non-smokers. The results are discussed in terms of recent evidence of reduced platelet MAO activity in psychiatric patients.