Pargyline, sold under the brand name Eutonyl among others, is a monoamine oxidase inhibitor (MAOI) medication which has been used to treat hypertension (high blood pressure) but is no longer marketed.
[1][12] Its onset of action is slow and several weeks of continuous administration are required for the effects to develop fully upon initiation of treatment.
[1] Pargyline shares its mechanism of action, monoamine oxidase inhibition, with a class of antidepressants that includes phenelzine, tranylcypromine, and isocarboxazid, among others.
[7][5] In any case, the drug was studied in the treatment of depression[7][8] and was advertised in the 1960s as an antihypertensive agent that also "brightens emotional outlook".
[1] Combination of pargyline and the antihypertensive agent methyldopa has been found to result in intense and potentially fatal central nervous system excitation in rodents.
[12][21][22] The interaction appears to be due to inhibition by pargyline of the metabolism of normally short-lived methyldopa metabolites like α-methyldopamine and α-methylnorepinephrine that act as potent catecholamine releasing agents.
[9][1][12] Another possibility is that pargyline increases levels of false neurotransmitters like octopamine and tyramine, which are weaker pressor agents than norepinephrine.
[9] In addition to its actions as an MAOI, pargyline has been found to bind with high affinity to the I2 imidazoline receptor.
[6][35] A high dose of pargyline (10 mg/kg) has been found to stimulate locomotor activity, a psychostimulant-like effect, in certain behavioral tests in rats.
[36][37] This might be due to its MAOI activity and increased dopamine levels in the nucleus accumbens or might be related to stimulant-like effects of its metabolites including benzylamine, N-methylbenzylamine, and/or N-propargylbenzylamine.
[36][38] Certain other MAOIs, like iproniazid, phenelzine, pheniprazine, and tranylcypromine, but not nialamide, have likewise been found to produce amphetamine- and psychostimulant-like effects at high doses in animals.
[3] The ALDH inhibition of pargyline appears to be mediated by its metabolites, namely propiolaldehyde, but also propargylamine and benzylamine.
[3][25] Pargyline has been found to act as a reversible inhibitor of diamine oxidase (DAO)-mediated putrescine metabolism.
[25][45][46] In contrast to selegiline, pargyline does not appear to show catecholaminergic activity enhancer (CAE)-like effects.
[26] The drug has been shown to elevate brain monoamine levels, for instance of serotonin norepinephrine, dopamine, and trace amines, in animals.
[50][51] Pargyline is N-demethylated and N-depropargylated by CYP2E1 to form arylalkylamine and other metabolites including benzylamine, N-methylbenzylamine, and N-propargylbenzylamine, among others.
[49][26] Pargyline preceded and is structurally related to the selective and irreversible MAO-B inhibitor selegiline (deprenyl; (R)-(–)-N-methyl-N-propargylamphetamine).