CHLORINATED ARYLALKYLAMINES AFFECTING THE CEREBRAL METABOLISM OF 5-HYDROXYTRYPTAMINE

¹ Medical and Chemical Research Departments, F. Hoffmann-La Roche & Co. Ltd., Basel, Switzerland

In the brain of rats and guinea pigs, a single intraperitoneal injection of dl-4-chloro-N-methyl-amphetamine (Ro 4-6861) slowly (decreases the endogenous 5-hydroxytryptamine (5HT) and 5-hydroxyindole acetic acid (5H1AA) 60 to 70% within 16 hours. The endogenous norepinephrine and dopamine are at the most slightly diminished by the drug, whereas endogenous homovanillic acid is decreased about 50%.

The 5-hydroxytryptophan-induced increase of 5HT in the brain of rats is slightly enhanced, whereas the rise of 5HIAA due to exogenous 5-hydroxytryptophan is slightly decreased by Ro 4-6861. The tryptophan-induced SHT elevation is not affected by the drug. Ro 4-6861 counteracts the 5HT accumulation due to the monoamine oxidase inhibitor pargyline.

The level of endogenous 5HT in the intestine of guinea pigs is not significantly changed, and the endogenous norepinephrine in the heart of rats and guinea pigs is only moderately decreased by Ro 4-6861.

Ro 4-6861 causes at the most a slight inhibition of decarboxylase of aromatic amino acids, monoamine oxidase, and tryptophan hydroxylase in vivo as well as of monoamine oxidase, dopamine--hydroxylase, and tryptophan hydroxylase in vitro.

Comparisons with various derivatives of Ro 4-6861 in rats indicate that the action of the drug on the cerebral 5HT is dependent on the chlorine in the aromatic ring. Ro 4-6861 reaches higher levels and lasts longer in the brain than amphetamine.

In conclusion, Ro 4-6861 causes a relatively specific, hitherto unknown type of 5HT decrease in the brain involving metabolic routes other than amine/aldehyde oxidation.

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