From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors

Prada, M. Da; Kettler, R.; Keller, H. H.; Cesura, Andrea M.; Richards, J. G.; Marti, J. Saura; Muggli-Maniglio, D.; Wyss, Pierre C.; Kyburz, E.; Imhof, R.

doi:10.1007/978-3-7091-9050-0_27

Cited by 55 publications

(54 citation statements)

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“…18) Regulation of MAO-A activity has been thought to be an effective approach for the treatment of depression and anxiety, while regulation of MAO-B appears to be helpful in the prevention and adjunct treatment of Parkinson's disease. 1,5) Although piperine showed a slightly more potent inhibitory effect on MAO-B than MAO-A, in vivo CNS depressant activity was also reported.…”

Section: Resultsmentioning

confidence: 99%

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

et al. 2005

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Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine, and appears to play important roles in several psychiatric and neurological disorders. 1,2) MAO has been divided into two subtypes, MAO-A and MAO-B, on the basis of their amino acid sequence, substrate and inhibitor selectivity, and tissue distribution.2-4) MAO-A inhibitors are useful in the therapy of mental disorders, mainly as antidepressants, whereas MAO-B inhibitors are expected to be useful in the therapy of Parkinson's and Alzheimer's disease. 1,5) To date, a number of MAO inhibitors such as coumarins, xanthones, and isoquinoline alkaloids have been isolated from natural products or synthesized. 6-9)Piper longum L. (Piperaceae), a slender aromatic climber, is a native of the Indo-Malayan region and grows wild in the tropical rain forests of India. The extract of the crude drug "Piperis Longi Fructus," the fruits of P. longum, is frequently used in folk medicine to treat bronchial trouble and is used as a carminative and analgesic. 10,11) Piperine was the first amide isolated from Piper species and was reported to display central nervous system depression, antipyretic, and anti-inflammatory activity. 12,13) Moreover, previous studies have demonstrated that piperine and its derivatives present sedative-hypnotic, tranquilizing, and muscle-relaxing actions and can intensify the depressive action of other depressants.14) Based on the aforementioned evidence, it might be suggested that piperine could be useful for the control of CNS-related conditions, including mood disorders and moderate or mild depression states.In the present work, we have investigated the activityguided isolation and inhibitory effect of piperine on MAO activity in mouse brain. We also investigate the antidepressant-like activity of piperine in the in vivo tail suspension test. Results and DiscussionIn our ongoing search for naturally occurring MAO inhibitors, an ethanol extract of the fruits of P. longum exhibited strong inhibitory activity on mouse brain MAO. A bioassay-guided isolation of the extract yielded a known piperidine alkaloid, piperine, as an active component. The structure was identified by physicochemical and spectroscopic methods (mp, UV, IR, MS, 1 H-and 13 C-NMR) and by comparing the data obtained with those of published values (Fig. 1). 15,16) Piperine exhibited 38.0% inhibition of MAO activity at 8 mM, with an IC 50 value of 11.1 mM, which is comparable to iproniazid as a positive control (Table 1). According to the kinetic properties of MAO from the mouse brain, the values of K m and V max by using kynuramine were 72.2Ϯ5.60 mM and 3.97Ϯ0.18 nmol/min/mg protein, respectively (nϭ3) (data not shown).In order to verify the selectivity of the MAO activity, l-deprenyl-pretreated MAO preparation was used for the measurement of MAO-A activity, whereas a clorgyline-pretreated preparation was used for MAO-B. This result indicated that

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Section: Resultsmentioning

confidence: 99%

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

et al. 2005

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“…In this respect, NAIBS appear to be associated with mitochondrial outer membranes and the density of these sites correlates well with MAO activity . However, the low affinity on NAIBS displayed by the selective (not propargylamines) MAO-A and MAO-B inhibitors, Ro 41-1049 (Cesura et al, 1990a;Da Prada et al, 1990) and Ro 16-6491 (Cesura et al, 1988;Cesura et al, 1990b), respectively; the lack of downregulation of NAIBS induced by chronic treatment with Ro 41-1049; and the much higher densities (40 to 75 times) of the two MAO isoenzymes (Saura et al, 1992) MAO. Recently, it has been reported that clorgyline also displays high affinity for the a (sigma) binding sites in the mouse brain (Itzkak & Kassim, 1990). However, the possibility of a direct link/interaction between [3H]-idazoxan and the a site was also discarded.…”

Section: Discussionmentioning

confidence: 99%

Chronic treatment with the monoamine oxidase inhibitors clorgyline and pargyline down‐regulates non‐adrenoceptor [³H]‐idazoxan binding sites in the rat brain

Olmos

Gabilondo

Miralles

et al. 1993

British J Pharmacology

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1 The binding of [3H]-idazoxan in the presence of 1O6 M (-)-adrenaline was used to quantitate non-adrenoceptor idazoxan binding sites (NAIBS) in the rat brain after treatment with various psychotropic drugs. 2 Chronic treatment (14 days) with the monoamine oxidase (MAO) inhibitors clorgyline (0.3-10mg kg-', i.p.) and pargyline (10mg kg-', i.p.), but not with Ro 41-1049 (1 mg kg-', i.p.), markedly decreased (30-50%) the density of NAIBS in the cerebral cortex without any apparent change in the affinity of the radioligand.3 Acute (1 day) and/or chronic treatments (14 days) with other psychotropic drugs such as desipramine 7 Together the results indicate that the irreversible binding of clorgyline and pargyline to NAIBS found in vitro does not fully explain the marked decreases in the density of NAIBS found in vivo after the chronic treatments. It is suggested that the down-regulation of NAIBS induced in vivo by clorgyline and pargyline, through a direct or indirect mechanism, may have functional implications.

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“…For this purpose we have studied the influence of pargyline, a non-selective MAO inhibitor, and of two selective MAO-A and MAO-B inhibitors, Ro 41-1049 and Ro 19-6327 respectively (Da Prada et al, 1990), on the outflow of newly-formed dopamine and of its deaminated metabolite DOPAC in slices of rat renal cortex loaded with exogenous L-DOPA. A preliminary account of some of these findings has been presented previously …”

Section: Introductionmentioning

confidence: 99%

Effect of type A and B monoamine oxidase selective inhibition by Ro 41–1049 and Ro 19–6327 on dopamine outflow in rat kidney slices

Pestana

Soares‐da‐Silva

1994

British J Pharmacology

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1 The influence of pargyline and of selective inhibitors of type A and B monoamine oxidase (MAO), Ro 41-1049 and Ro 19-6327 respectively, on the outflow of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in slices of rat renal cortex loaded with exogenous L-3,4-dihydroxyphenylalanine (L-DOPA) was examined. Dopamine and DOPAC in the tissues and in the effluent were assayed by means of h.p.l.c. with electrochemical detection. 2 The levels of newly-formed dopamine and DOPAC in the perifusate decreased progressively with time. In control conditions, DOPAC/dopamine ratios in the perifusate were 3 to 5 fold those in the tissue and were found to increase progressively with time. The addition of pargyline (100 ItM), produced a marked decrease in the outflow levels of DOPAC (45 to 54% reduction) and significantly increased the levels of dopamine in the effluent (102 to 158% increase); DOPAC/dopamine ratios in the perifusate remained stable throughout the perifusion and were similar to those found in the tissues. The addition of the MAO-A inhibitor Ro 41-1049 to the perifusion fluid also significantly decreased DOPAC outflow (41% to 54% reduction) and increased dopamine outflow (19% to 80% increase). In the presence of Ro 41-1049 DOPAC/dopamine ratios in the perifusate were lower (P<0.01) than in controls; in contrast with the effect of pargyline, this ratio was found to increase (P < 0.01) throughout the perifusion period. Ro 19-6327 did not reduce the outflow of DOPAC, but significantly increased (by 40-60%) that of dopamine. In the presence of Ro 19-6237, the proportion of DOPAC to dopamine in the perifusate was similar to that of controls and significantly increased throughout the perifusion; however, this increase was less than that observed in the control group. 3 When benserazide (50 JAM) was added to the perifusion fluid, the levels of both dopamine and DOPAC in the effluent were similar to those observed in the absence of benserazide. However, in the presence of benserazide, DOPAC/dopamine ratios in the perifusate did not increase with time. In conditions of decarboxylase inhibition, the effects of pargyline, Ro 41-1049 and Ro 19-6327 on dopamine and DOPAC outflow were less pronounced than in experiments conducted in the absence of benserazide. 4 In conclusion, the results presented here show that the fraction of newly-formed dopamine which leaves the compartment where the synthesis has occurred is a constant source for deamination into DOPAC. The results provide evidence favouring the view that MAO-A is the main form of the enzyme involved in this process; however, the data described here suggest that dopamine would also have access to MAO-B.

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From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors

Cited by 55 publications

References 13 publications

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Chronic treatment with the monoamine oxidase inhibitors clorgyline and pargyline down‐regulates non‐adrenoceptor [³H]‐idazoxan binding sites in the rat brain

Effect of type A and B monoamine oxidase selective inhibition by Ro 41–1049 and Ro 19–6327 on dopamine outflow in rat kidney slices

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From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors

Cited by 55 publications

References 13 publications

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Chronic treatment with the monoamine oxidase inhibitors clorgyline and pargyline down‐regulates non‐adrenoceptor [3H]‐idazoxan binding sites in the rat brain

Effect of type A and B monoamine oxidase selective inhibition by Ro 41–1049 and Ro 19–6327 on dopamine outflow in rat kidney slices

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Chronic treatment with the monoamine oxidase inhibitors clorgyline and pargyline down‐regulates non‐adrenoceptor [³H]‐idazoxan binding sites in the rat brain