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Selective inhibition by amiflamine of monoamine oxidase type A in rat brain, liver and duodenum
Abstract:
Amiflamine (FLA 336(+)), N-desmethylamiflamine (FLA 788(+)) and N,N-didesmethylamiflamine (FLA 668(+)) were examined for their monoamine oxidase (MAO) inhibitory effects in rat brain, liver and duodenum and were compared with the irreversible inhibitors clorgyline and (-)-deprenyl. The potency of each FLA compound was the same in each tissue both in vitro and after oral administration with either serotonin or tyramine as substrate. The in vitro effect of FLA 788(+) was 2-6 times stronger than that of amiflamine although the compounds were equipotent after oral administration. FLA 668(+) was 2-3 times less potent than amiflamine in vitro and had very poor activity after oral administration. The deamination of phenethylamine was weakly affected by the three FLA compounds. Clorgyline inhibited strongly the deamination of serotonin and tyramine in the duodenum after oral administration, being 1,000 times more potent than in the brain and the liver. Similar results were obtained for (-)-deprenyl which, however, was more potent in inhibiting the deamination of phenethylamine than that of serotonin and tyramine. Amiflamine was a reversible MAO inhibitor with no MAO inhibitory capacity 24 h after a single oral dose. On the other hand the irreversible inhibitor clorgyline had a maximal effect on brain MAO 48 h after a single dose while the inhibitory effect in the duodenum had almost disappeared. The influence of amiflamine on the excretion of acid and basic metabolites of orally administered 14C-tyramine (58 mumol/kg) in rat was examined.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Amiflamine and its derivatives are reversible monoamine oxidase (MAO) inhibitors, showing varying potency in different tissues. Unlike irreversible inhibitors, amiflamine
Area of Science:
- Pharmacology
- Biochemistry
- Neuroscience
Background:
- Monoamine oxidase (MAO) enzymes are crucial for neurotransmitter metabolism.
- Selective MAO inhibitors are used therapeutically, but their tissue-specific effects and reversibility vary.
- Amiflamine and its derivatives (FLA 788(+), FLA 668(+)) were investigated for their MAO inhibitory properties.
Purpose of the Study:
- To compare the MAO inhibitory effects of amiflamine, N-desmethylamiflamine, and N,N-didesmethylamiflamine in rat tissues.
- To evaluate the reversibility and tissue-specific potency of these compounds.
- To compare their effects with irreversible MAO inhibitors, clorgyline and (-)-deprenyl.
Main Methods:
- In vitro and in vivo assessment of MAO inhibition in rat brain, liver, and duodenum.
- Use of serotonin, tyramine, and phenethylamine as substrates.
- Oral administration of FLA compounds and irreversible inhibitors.
- Examination of metabolite excretion after 14C-tyramine administration.
Main Results:
- Amiflamine and its derivatives exhibited consistent potency across tissues in vitro and after oral administration.
- FLA 788(+) was more potent in vitro than amiflamine, but equipotent orally.
- FLA 668(+) showed lower in vitro and oral potency compared to amiflamine.
- Amiflamine demonstrated reversible MAO inhibition, with no activity after 24 hours.
- Clorgyline showed potent, time- and tissue-dependent inhibition, particularly in the duodenum.
Conclusions:
- Amiflamine is a reversible MAO inhibitor with distinct pharmacokinetic and pharmacodynamic properties compared to irreversible inhibitors.
- The FLA compounds display differential potency and tissue distribution of MAO inhibition.
- Understanding these differences is crucial for developing selective MAO-targeting therapies.