Tse W. Hall

Detection and quantitation of a ring-hydroxylated metabolite of the antidepressant drug tranylcypromine

The formation ofp-hydroxytranylcypromine from intraperitoneally injected tranylcypromine was confirmed using two types of experiments. In the first, tranylcypromine levels were shown to be increased in brains of rats pretreated with agents known to be inhibitors of ring hydroxylation compared to rats pretreated with physiological saline. For the second set of experiments,p-nydroxytranylcypromine was identified in brain and urine (following intraperitoneal injection) by derivatizing with perfluoroacylating reagents and analyzing by electron-capture gas chromatography and by combined gas chromatography-mass spectrometry. In experimentsin vitro, p-hydroxytranylcypromine was demonstrated to inhibit monoamine oxidase, although it was weaker than TCP in this regard and was a much stronger inhibitor of MAO-A than of MAO-B.

Neurochemical and neuropharmacological properties of 4-Fluorotranylcypromine

Summary1.The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and Bin vitro andex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine.2.4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and Bin vitro in rat brain homogenates.3.After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount.4.At the dose employed, theex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other.5.Although the drugs had similar effects on inhibition of brain MAOex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain.6.In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAOin vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.

Tranylcypromine and an N-Cyanoethyl Analogue: Effects on Brain Levels of the Trace Amines β-Phenylethylamine and Tryptamine

Imbalances in the neuronal homeostasis of the trace amines β-phenylethylamine (PE) and tryptamine (T) have been implicated in the aetiology of certain neuropsychiatry disorders, including depression (Dewhurst, 1984 for review). Tranylcypromine (TCP), a monoamine oxidase (MAO) inhibitor used clinically as an antidepressant, has been shown to elevate substantially brain concentrations of these trace amines (Philips and Boulton, 1979). A number of N-alkylated derivatives of TCP have been synthesized in our laboratories to test them as potential prodrugs of TCP. The prodrug N-(2-cyanoethyl)tranylcypromine (CE-TCP) was found to be a potent MAO inhibitor in its own right (Baker et al., 1984). A neurochemical study is now reported in which the effects of TCP and CE-TCP on brain levels of the trace amines PE and T are compared.