The prevention by six reversible and selective monoamine oxidase-A (MAO-A) inhibitors (alpha-ethyl-tryptamine, harmaline, 4-methoxyamphetamine, amiflamine [FLA 336(+)], N-desmethylamiflamine [FLA 788(+)] and N,N-desmethylamiflamine [FLA 668(+)] of the phenelzine-induced irreversible MAO inhibition in the rat brain was examined. By using crude synaptosome preparations of hypothalamus and striatum incubated with low substrate concentrations of 14C-serotonin (1 X 10(-7) M), 14C-noradrenaline (2.5 X 10(-7) M) and 14C-dopamine (2.5 X 10(-7) M) in the absence and presence of selective amine uptake inhibitors (alaproclate, maprotiline and amfonelic acid, respectively), it was possible to determine the deaminating activities inside and outside the specific aminergic synaptosomes. Thus, with this technique the protection of MAO by the reversible inhibitors administered orally 1 h prior to the subcutaneous injection of phenelzine against the phenelzine effect could be determined inside and outside the specific aminergic neurons. It was found that alpha-ethyltryptamine, 4-methoxyamphetamine and particularly amiflamine and FLA 788(+) were more potent inside than outside the serotonergic neurons. FLA 668(+) was a selective inhibitor of noradrenergic MAO, to which also 4-methoxyamphetamine, amiflamine and FLA 788(+), but not alpha-ethyltryptamine had some preference. Harmaline had no certain preference for MAO in any of the aminergic neurons. At high doses of FLA 668(+) a preference for dopaminergic MAO was observed. Since pretreatment of the rats with norzimeldine or desipramine antagonized the preferences for serotonergic or noradrenergic MAO, it is plausible to conclude that the compounds showing these preferences are accumulated in the neurons by the membranal uptake systems.

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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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