Philippe Dostert

Is the oxidation of milacemide by monoamine oxidase a major factor in its anticonvulsant actions

The anticonvulsant drug milacemide (2-n-pentylaminoacetamide) is known to be oxidized by monoamine oxidase-B to yield glycinamide which then breaks-down to give glycine. It has been postulated that it is this liberation of glycine in the brain that accounts for the anticonvulsant effects. In order to test this hypothesis, and since amines bearing a methyl-group in the alpha-position have been shown to be resistant to oxidation by monoamine oxidase, the effects of milacemide were compared with those of alpha-methyl-milacemide. Although the latter compound was found to be toxic at higher concentrations, it was found to antagonize bicuculline-induced convulsions in mice. When milacemide was administered to mice (0.5 mmol/kg, p.o.) there was a substantial increase in urinary glycinamide excretion. No such increase was observed after the administration of the same dose of alpha-methyl-milacemide. Furthermore, alpha-methyl-milacemide was not oxidized by either monoamine oxidase-A or -B in vitro to any detectable extent, although it was a competitive inhibitor of both forms of the enzyme. The findings that alpha-methyl-milacemide has anticonvulsant properties in the bicuculline test but is not a substrate for monoamine oxidase or a source of urinary glycinamide cast doubt on the importance of the oxidation or milacemide to form glycinamide as a major factor in its anticonvulsant action.

Early markers in Parkinson's and Alzheimer's diseases

The aim of this study is to provide the reader with updated data on various approaches whose investigation and development could contribute to the discovery of early diagnostic markers of these two degenerative diseases. Concerning Parkinsons disease, some of the topics dealt with in the book aim to update information previously reported in other texts. Concerning Alzheimers disease, the scope and limitations of electrophysiological and brain imaging techniques with regard to early detection of the disease are documented. Various biochemical parameters, such as brain energy metabolism, levels of choline and platelet monoamine oxidase activity are envisaged as some of the starting points for the discovery of early diagnostic markers.

Species differences in the interactions of the anticonvulsant milacemide and some analogues with monoamine oxidase-B

Oxidation of the anticonvulsant drug milacemide [2-n-(pentylamino)acetamide] by monoamine oxidase-B (MAO-B) has been reported to be important in terminating its activity. Comparison of the oxidation of this compound by MAO-B preparations from ox and rat liver showed the former enzyme to have a significantly higher Km value towards this substrate. In keeping with this, the Ki values for milacemide acting as a competitive inhibitor of these enzymes showed it to have a lower affinity for ox liver MAO-B. Comparative studies on the time-dependent inhibition of the two enzymes also showed a lower sensitivity of that from the ox liver. Studies with a series of analogues involving replacement of pentylamino group of milacemide showed marked differences between the sensitivities of the two enzymes. The largest differences were shown by the compound 2(4-(3-chlorobenzoxy)phenethylamino)acetamide which gave IC50 values of 0.051 +/- 0.008 and 4.1 +/- 0.8 microM with the rat and ox enzymes, respectively, when activities were assayed without prior enzyme-inhibitor preincubation. When the enzyme and inhibitor were incubated for 60 min at 37 degrees before assay these values fell to 0.027 +/- 0.002 and 3.5 +/- 0.4 microM, respectively. These marked differences prompted a study of the inhibition of MAO-A and MAO-B from human liver and brain, mouse brain and rat brain as well as MAO-B from ox liver by milacemide and alpha-methylmilacemide. There were no significant differences in the sensitivities of any of the mitochondrial MAO-A preparations studied towards these compounds. However, MAO-B from human brain and liver mitochondrial resembled that from ox liver in being less sensitive to inhibition than the rat and mouse enzymes. Purification of the ox liver MAO-B did not significantly affect its interactions with milacemide and alpha-methylmilacemide. The marked species differences reported here raise questions concerning the validity of rodent model systems, that have frequently been used for assessing the in vivo and in vitro actions of milacemide and its analogues, for the situation in the human.

Clinical pharmacology of the new COMT inhibitor CGP 28 014

CGP 28 014 is a specific inhibitor of catechol-O-methyltransferase (COMT) in vivo. In humans, the inhibition was assessed by measuring urinary excretion of isoquinolines and with the levodopa test. Following administration of CGP 28 014, urinary excretion of isoquinolines was significantly increased. In rats, CGP 28 014 reduced plasma and striatal concentrations of 3-O-methyldopa (30MD) in a dose-dependent manner. Acute and subchronic administration of CGP 28 014 alone or in combination with the peripherally acting decarboxylase inhibitor benserazide decreased plasma 30MD as an index of COMT inhibition by about 50%. There seems to be a close relationship between the time-course of plasma concentrations of CGP 28 014 and the extent of COMT inhibition assessed by the 30MD/DOPA ratio in plasma.

Synthesis of the R and S enantiomers of 1,2,3,4-tetrahydro-6,7-dihydroxy-1-methylisoquinoline-1-carboxylic acid

Abstract 1,2,3,4-Tetrahydro-6,7-dihydroxy-1-methylisoquinoline-1-carboxylic acid (salsolinol-1-carboxylic acid) has been shown to be a bioprecursor of ( R )-salsolinol in humans. We report here a synthesis and the determination of the absolute configurations of both enantiomers of salsolinol-1-carboxylic acid.

Synthesis of new fenmetazole analogues with potential mixed α2-adrenergic antagonistic activity and noradrenaline-uptake inhibiting properties

Abstract In the search for new antidepressants with a rapid onset of action, fenmetazole analogues, bearing a second phenyl ring in a position previously shown not to be detrimental to affinity and selectivity for the α 2 -adrenoreceptors, were synthesized in an attempt to combine NA-uptake inhibition and blockade of the α 2 -adrenoreceptors in the same molecule. Some of the new molecules showed enhanced affinity and selectivity for the α 2 -adrenoreceptors compared to fenmetazole. Surprisingly, introduction of a phenyl ring in the structure of fenmetazole changed the agonistic action of the parent compound toward the α 1 -adrenoreceptors into an antagonistic effect. However, none of the new derivatives showed in vitro NA-uptake inhibitory potency substantially different from the low activity of fenmetazole in this test.

Research of potential antidepressant drugs with α2-adrenoreceptor antagonist and NA-uptake inhibiting properties: synthesis of 2-(1-hydroxy-2-phenoxy-2-phenyl)ethyl-4,5-dihydro-1H-imidazole derivatives

Abstract A series of 2-(1-hydroxy-2-phenoxy-2-phenyl)ethyl-4,5-dihydro-1 H -imidazole derivatives has been synthesized with the aim of finding potential antidepressant drugs endowed with both NA-uptake and α 2 -antagonist properties. The structure of the new compounds was designed by mixing the common elements present in reboxetine and α-aryloxy-benzyl derivatives of ethanolamine, both having NA-uptake inhibitory properties in vitro , and in idazoxan, a potent and selective α 2 -adrenoreceptor antagonist. The new hybrids allow a good fitting of the common features without the strong steric interactions occurring when the structure of reboxetine is superimposed on that of idazoxan. However, the new derivatives did not display significant interaction with the NA-uptake system and the α 2 -adrenoreceptors and proved inactive in the antireserpine test taken as a model of potential antidepressant activity. The possible relationship between the structural changes made in the parent molecules and the complete loss of activity on both systems is discussed.

Effect of Selegiline Administration on the Urinary Excretion of Dopamine-Derived Tetrahydroisoquinoline Alkaloids in Parkinson’s Disease Patients

It has long been suggested that, in humans, the biosynthesis of salsolinol (Sal), a dopamine (DA)-derived isoquinoline alkaloid, might occur by condensation of DA with acetaldehyde or with pyruvic acid followed by oxidative decarboxylation and reduction (Figure 1). Sal possesses an asymmetric center at C-1 and exists as R and S enantiomers. There is supportive evidence that, at least in healthy subjects under physiological conditions, Sal biosynthesis should result from the condensation of DA with pyruvic acid: 1) 1-carboxysalsolinol and 1,2-dehydrosalsolinol (DSal) have been detected in human brain and urine together with Sal (Sjoquist and Ljungquist, 1985; Ung-Chhun et al., 1985; Dostert et al., 1990a); and 2) the presence of only the R enantiomer of Sal in urine of healthy subjects (Dostert et al., 1991) would not be consistent with this compound arising from the non-enzymic condensation of DA with acetaldehyde.

Tetrahydroisoquinoline Alkaloids in Neurodegenerative Disorders - Influence of Drug Treatment

The presence of various 1,2,3,4-tetrahydroisoquinoline alkaloids in the human brain has been firmly established1–5 and the possible involvement of these alkaloids in the etiology of some neurodegenerative disorders, such as Parkinson’s disease, or in the craving for alcohol has been the object of many investigations and hypotheses.4–8