Selective inhibition of the a form of monoamine oxidase by 4-dimethylamino-α-methylphenylalkylamine derivatives in the rat

Ask, Anna‐Lena; Hellström, Wera; Norrman, S R; Ögren, Sven Ove; Ross, Svante B.

doi:10.1016/0028-3908(82)90092-2

Cited by 32 publications

(13 citation statements)

References 11 publications

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“…Although all these previous studies used decapitation to sacrifice the animals, there have been some discrepancies in their results. Moreover, the results of some studies (11,13,20) are consistent with those of the present study using microwave irradiation to sacrifice the animals. Hence the inconsistency between the results of the previous studies and those of the present study cannot be explained simply by the difference in the methods used to sacrifice animals.…”

Section: Discussionsupporting

confidence: 91%

“…although to only a small degree, in the deamination of NE and DA in the cortex only when MAO-A is inhibited. Increases in monoamines by moclobemide and clorgyline, but not by deprenyl, have already been described (9,11,13,(18)(19)(20). Furthermore, exclusive deamination of monoamines by MAO-A has already been suggested for DA in the striatum (11), NE in the hypothalamus and brainstem (12), and NE (8,9,12,16), DA (8,12,16), and 5HT (8,9,16) in the whole brain; and the participation of MAO-B only when MAO-A is inhibited has also been suggested for NE in the hypothalamus and caudate nucleus (13) and 5HT in the hypothalamus and mesencephalic raphe nuclei (19).…”

Section: Discussionmentioning

confidence: 89%

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Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359.

Kumagae¹,

Matsui²,

Iwata³

1991

Jpn.J.Pharmacol

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ABSTRACT-Levels of monoamines and their metabolites were determined in the cortex, hippocampus, and striatum of rats killed by microwave irradiation. Moclobemide (20 mg/kg, p.o.) and clorgyline (10 mg/kg, p.o.), type A monoamine oxidase (MAO-A) inhibitors, increased the levels of normetanephrine (NM) and 3-methoxytyramine (3MT) and decreased those of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) in almost all three regions. Deprenyl (10 mg/kg, p.o.), a type B monoamine oxidase inhibitor, however, little affected monoamine and metabolite levels in all regions. The maximum effects of RS-8359 (10 mg/kg, p.o.) were obtained at 2 to 6 hr after administration, when the levels of norepinephrine (NE), NM, 3MT, and serotonin (5HT) in all regions and dopamine (DA) in the striatum increased, while DOPAC and HVA levels decreased. The levels of monoamines and metabolites had returned to normal by 20 hr after administration. Dose-dependency of the effects of RS-8359 on monoamine metabolites was observed at doses up to 30 mg/kg (p.o.) at 1 and 6 hr after administration. In conclusion, NE, DA, and 5HT are exclusively or preferentially deaminated by MAO-A in the cortex, hippocampus, and striatum of rats, and RS-8359 exhibits a reversible MAO-A inhibitory action in all three regions tested in vivo.Monoamine oxidase (MAO), which is responsible for deamination of norepinephrine (NE), dopamine (DA), and serotonin (5HT), is classified into two forms: MAO-A and MAO-B, each of which can be defined by its sensitivity to inhibition by clorgyline (an MAO-A inhibitor) or deprenyl (an MAO-B inhibitor) (1-3).RS-8359 ((±)-4-(4-cyanoanilino)-7-hydroxycyclopenta(3,2-e)pyrimi dine) is reported to be a highly selective and reversible MAO-A inhibitor from in vitro experiments (4, 5). The in vivo effectiveness of a reversible MAO-A inhibitor in the brain can be evaluated from the inhibitor-induced changes in the brain levels of monoamines and/or their metabolites (1); RS-8359 has already been shown to increase monoamine levels and to decrease deaminated metabolite levels in mouse whole brain (4). However, in order to estimate exactly the in vivo effect of RS-8359 on MAO-A, its effect on monoamine and metabolite levels must be determined in discrete regions of the brain, since monoamines are unevenly distributed in the brain (6, 7). Moreover, the degree to which MAO-A contributes to the deamination of monoamines in discrete brain regions in vivo remains obscure, since most

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 89%

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359.

Kumagae¹,

Matsui²,

Iwata³

1991

Jpn.J.Pharmacol

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“…The inhibition of rat brain mitochondrial MAO in vitro was determined as described by Ask et al (1982b) The deamination of ['4C]-5-HT by the synaptosomal preparation was determined as described previously (Ask et al, 1983) with some modifications. Fifty microlitres of the synaptosomal preparation, corresponding to 2.5 mg wet weight of tissue, was added to glass-stoppered centrifuge tubes containing 925 gi of Krebs-Henseleits buffer, pH 7.4, equilibrated with 93.5% 02 and 6.5% CO2, and containing glucose 5.6 mM, ascorbic acid 1.1 mM, Na2 EDTA 0.…”

Section: Methodsmentioning

confidence: 99%

“…Hence, a compound has to fulfil two requirements in order to be a neuronally selective MAO inhibitor in a specific amine system: it has to be (1) a potent MAO-A inhibitor and (2) transported by the amine pump. In the present study we have reexamined a series of previously published compounds structurally related to amiflamine (Florvall et al, 1978;Ask et al, 1982b) with regard to their inhibitory action on MAO in 5-hydroxytrypaminergic nerve terminals in the rat hypothalamus in vivo. In a separate study the corresponding effects on MAO in catecholaminergic nerve terminals are described .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of monoamine oxidase in 5‐ hydroxytryptaminergic neurones by substituted p‐aminophenylalkylamines

Ask

Fagervall

Florvall

et al. 1985

British J Pharmacology

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1 A series of substituted p-aminophenethylamines and some related compounds were examined with regards to the inhibition ofmonoamine oxidase (MAO) in vivo inside and outside 5-hydroxytryptaminergic neurones in the rat hypothalamus. This was recorded as the protection against the irreversible inhibition of MAO produced by phenelzine by determining the remaining deaminating activity in the absence and presence of citalopram using a low (0.1 yIM) concentration of ['4CJ-5-hydroxytryptamine (5-HT) as substrate. 2 Some of the phenethylamines were much more potent inside than outside the 5-hydroxytryptaminergic neurones. This neuronal selectivity was antagonized by pretreatment of the rats with norzimeldine, a 5-HT uptake inhibitor, which indicates that these compounds are accumulated in the 5-HT nerve terminals by the 5-HT pump. 3 Selectivity was obtained for compounds with dimethyl, monomethyl or unsubstituted p-amino groups. An isopropyl group appears to substitute for the dimethylamino group but with considerably lower potency. Compounds with 2-substitution showed selectivity for aminergic neurones and this effect decreased with increased size of the substituent. The 2,6-dichloro derivative FLA 365 had, however, no neuronal selective action but was a potent MAO inhibitor. Substitutions in the 3-and 5-positions decreased both potency and selectivity. 4 Prolongation of the side chain with one methylene group abolished the preference for the MAO in 5-hydroxytryptaminergic neurones although the MAO inhibitory potency remained. The selectivity disappeared by increasing the a-substituent to an ethyl group but remained for the oco-dimethyl substituted derivatives. 5 It is concluded that compounds which are (1) transported by the 5-HT pump and (2) potent reversible MAO-A inhibitors produce pronounced inhibition of MAO in 5-hydroxytryptaminergic neurones.

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“…However, a maximal increase in rat brain 5-HT is produced by amiflamine (3.8 mg/kg, p.o.) at 4-8 hr after adminis tration (20). So, experiments were started at 3 hr after the final administration of ami flamine in this study.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Amiflamine, a Reversible MAO-A Inhibitor, on the First Pass Metabolism of Tyramine in Dog Intestine

Yasuhara

Kiuchi

Oguchi

et al. 1986

Japanese Journal of Pharmacology

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Abstract-The effects of amiflamine on tyramine deamination were studied using isolated loops of intestine in anesthetized dogs.In the pretreatment experiment, dogs were dosed with amiflamine (3.5 mg/kg/day) once daily for 3 days, with the study being carried out 3 hr after the final dose.[14C] Tyramine (50 mg and 50 /cCi) in 10 ml of normal saline was introduced into the isolated loops of gut, and tyramine and p-hydroxyphenylacetic acid in the venous blood were separated by HPLC and measured by scintillation spectrometry.In the untreated dogs, ap proximately 15% of the tyramine passed through the gut wall unchanged. When tyramine and amiflamine (0.06 to 3.5 mg/kg) were administered simultaneously to the gut loop, about 27 to 65% of the tyramine passed through the gut wall un changed.On the contrary, after pretreatment with amiflamine for 3 days, percen tage of tyramine passing through the gut wall was not increased in comparison with the control.These results suggest that pretreatment with amiflamine does not produce drug concentrations in the lining cells of the gut sufficient to effectively inhibit the deamination of oral tyramine, which is administered at least 3 hr after the final dose of amiflamine.Monoamine oxidase (MAO) inhibitors are clinically used as antidepressants, but limitation of extensive use of these drugs is due to hypertensive crisis (cheese effect) occurring when the patient ingests certain foodstuff containing vasoactive amines such as tyramine. Circulating tyramine liberates noradrenaline from nerve endings and produces the pressor effect (1 ). It is generally assumed that such hypertensive crises occur as a result of inhibition of MAO in the intestine and to a lesser extent in the liver, allowing active tyramine to enter the systemic circulation, and of inhibition of intraneural

show abstract

Selective inhibition of the a form of monoamine oxidase by 4-dimethylamino-α-methylphenylalkylamine derivatives in the rat

Cited by 32 publications

References 11 publications

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359.

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359.

Inhibition of monoamine oxidase in 5‐ hydroxytryptaminergic neurones by substituted p‐aminophenylalkylamines

The Effects of Amiflamine, a Reversible MAO-A Inhibitor, on the First Pass Metabolism of Tyramine in Dog Intestine

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