Overview of the present state of MAO inhibitors

Benedetti, Μ. Strolin; Dostert, P.

doi:10.1007/978-3-7091-8901-6_7

Cited by 12 publications

(6 citation statements)

References 35 publications

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“…MAO exists in two forms: MAO-A and MAO-B. The two enzymes differ in their distribution in bodily tissues, their sensitivity to different inhibitors and their substrate specificity (Schoepp and Azzaro, 1981;Copper et al,1991;Strolin Benedetti and Dostert, 1987;Saura et al,1992). MAO-A preferentially metabolizes 5-HT: the Km value of 5-HT for MAO-A is about 200 µM (Robinson, 1985;Gerlach et al,1992) and is about 2 mM for MAO-B (Gerlach et al,1992).…”

Section: Introductionmentioning

confidence: 99%

Is phentermine an inhibitor of monoamine oxidase? A critical appraisal

Rothman¹

1999

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Phentermine produces a spectrum of concentration-dependent biochemical effects. It interacts with NE transporters at 0.1 microM, DA transporters at about 1 microM, 5-HT transporters at 15 microM and MAO-A at about 100 microM. When administered at typical anorectic doses, phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting MAO-A. Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5-HT, since platelet MAO-B does not metabolize platelet 5-HT, and since amphetamine-type drugs are even weaker inhibitors of MAO-B than MAO-A. Clinical studies in humans have shown that amphetamine, which is a more potent inhibitor of MAO-A than phentermine, does not inhibit MAO-A at therapeutic doses. Neither phentermine alone, fluoxetine alone or their combined use have been associated with cardiac valvulopathy, and clinical experience has shown their combined use to be free of significant adverse effects. Viewed collectively, there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses.

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Section: Introductionmentioning

confidence: 99%

Is phentermine an inhibitor of monoamine oxidase? A critical appraisal

Rothman¹

1999

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“…A reasonable correlation was indeed found for these four substrate analogues. Extension of these correlations to known inhibitors of MAO A include the R and S isomers of amphetamine (22) and the (-)-and (+)-trans isomers of phenylcyclopropylamine (23). The correlation is shown in Figure 5 where a linear correlation of log K d with E s is found for binding affinities spanning over a 10 4 -fold range.…”

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confidence: 95%

Structure−Activity Relations in the Oxidation of Phenethylamine Analogues by Recombinant Human Liver Monoamine Oxidase A

Nandigama

Edmondson

2000

Biochemistry

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The interaction of recombinant human liver monoamine oxidase A (MAO A) with a series of phenethylamine substrate analogues has been investigated by steady-state and stopped-flow kinetic techniques. Substrate analogues with para substituents exhibit large deuterium kinetic isotope effect on k(cat), on k(cat)/K(m), and on the limiting rate of enzyme reduction in reductive half-reaction experiments. These kinetic isotope effect values range from 5 to 10 with the exception of tyramine, which exhibited smaller steady-state isotope effects (2.3-3.5) than that observed on the rate of flavin reduction (6.9). The stopped-flow data show that imine release from the reduced enzyme is slower than the rate of catalytic turnover. Phenethylamine oxidation by MAO A can be described as the C-H bond cleavage step being rate limiting in catalysis and with oxygen reacting with the reduced enzyme-imine complex. In the case of tyramine, the product release from the oxidized enzyme-imine complex contributes to the rate limitation in catalysis. The binding affinities of a series of para-substituted phenethylamine analogues to MAO A show an increase in affinity of the deprotonated amine with increasing van der Waals volume of the substituent. The limiting rate of enzyme reduction decreases with increasing van der Waals volume of the substituent in a linear manner with no observable electronic contribution as observed previously with benzylamine reduction of MAO A [Miller, J. R., and Edmondson, D. E. (1999) Biochemistry 38, 13670-13683]. Examination of side chain analogues of phenethylamine show 3-phenylpropylamine to be oxidized 2.5-fold more slowly and bound 75-fold more tightly than phenethylamine. 4-Phenylbutylamine is not a substrate for MAO A but is a good competitive inhibitor with a K(i) value of 31 +/- 5 microM. Analysis of the effect of alkyl side chain alterations on binding affinities of a series of arylalkylamine analogues taken from this study and from the literature show a linear correlation with the Taft steric value (E(s)) of the side chain. These results suggest that the binding site for the aryl ring is identical for phenethylamine and for benzylamine analogues and that steric interactions of the alkyl side chain with the enzyme strongly contribute to the binding affinities of a series of reversible inhibitors of MAO A.

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“…IFO produced time-independent inhibition, but its binding to the mitochondrial fraction was quite tight with no change after dialysis (or washing) with buffer. If MAO-B catalyzed the conversion of IFO in the same man ner as its conversion of other irreversible inhibitors (17), which have been divided into four chemical types: sub stituted hydrazine, cyclopropylamine, propargylamine and allylamine derivatives, IFO and its product would covalently bind to the active site of this enzyme (17). However, covalent binding is not supported by the fact that the tight binding behavior of IFO, as shown in the Henderson plot (16), disappears in the presence of so dium cholate, which causes the inhibitor to dissociate from the enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Considering this dis parity, one must determine if IFO may be carried away from the tissue or if it is possibly metabolized in vivo. The reversibility of IFO may be a unique feature as compared to the characteristics of known reversible and irreversible MAO inhibitors (1,17).…”

Section: Discussionmentioning

confidence: 99%

A Study of the Biological Pharmacology of IFO, a New Selective and Reversible Monoamine Oxidase-B Inhibitor.

et al. 1994

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propoxy]phenyl]-5-trifluoromethyl-1,2,4-oxadiazole (IFO), design ed to be a novel selective inhibitor of monoamine oxidase (MAO), showed highly selective inhibition for type-B (MAO-B); its IC50 was approximately > 200 pM and 30 nM for type-A (MAO-A) and MAO-B, respectively, in the standard assay using mitochondrial preparations from rat brain or liver. The in vitro MAO-B inhibition by IFO was time-independent, non-competitive and tight-binding; and furthermore, in the presence of sodium cholate its inhibition was not tight-binding and was reversible. Oral administration of IFO (0.5 -100 mg/kg) produced a dose-dependent MAO-B inhibition in mouse brain; its ED50 (p.o., 1 hr) was 1.6 mg/kg, while L-deprenyl inhibited the enzyme with the ED50 of approximately 8.0 mg/kg. The ED50 for MAO-A was > 100 mg/kg for either IFO and L-deprenyl. The MAO inhibitive effect of IFO in mouse liver was the same as that in the brain, but that of L-deprenyl in mouse liver was different from that in the brain as shown by the ED50 values of 35 mg/kg and 0.6 mg/kg for MAO-A and MAO-B, respectively. In mice, IFO increased the striatal concentrations of 2-phenylethylamine (2-PEA) and showed almost the same protective efficacy as L-deprenyl against the lethality and striatal dopamine (DA) depletion induced by 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results indicate that IFO appears to be a potent inhibitor of MAO-B in mouse brain.

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Overview of the present state of MAO inhibitors

Cited by 12 publications

References 35 publications

Is phentermine an inhibitor of monoamine oxidase? A critical appraisal

Is phentermine an inhibitor of monoamine oxidase? A critical appraisal

Structure−Activity Relations in the Oxidation of Phenethylamine Analogues by Recombinant Human Liver Monoamine Oxidase A

A Study of the Biological Pharmacology of IFO, a New Selective and Reversible Monoamine Oxidase-B Inhibitor.

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