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| Trade names | Eutonyl; Eutron |
| Other names | MO-911; A-19120; Lopac-P-8013; NSC-43798;N-Methyl-N-propargylbenzylamine |
| MedlinePlus | a682088 |
| Routes of administration | Oral[1][2] |
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| Metabolites | •N-Methylbenzylamine[3] •N-Propargylbenzylamine[3] •N-Methylpropargylamine[3] •Benzylamine[3] •Propiolaldehyde[3] •Propargylamine[3] •Benzaldehyde[3] • Pargyline-N-oxide[3] |
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| ECHA InfoCard | 100.008.275 |
| Chemical and physical data | |
| Formula | C11H13N |
| Molar mass | 159.232 g·mol−1 |
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Pargyline, sold under the brand nameEutonyl among others, is amonoamine oxidase inhibitor (MAOI)medication which has been used to treathypertension (high blood pressure) but is no longer marketed.[4][5][6] It has also been studied as anantidepressant, but was never licensed for use in the treatment ofdepression.[7][8] The drug is takenby mouth.[1][2]
Side effects of pargyline includeorthostatic hypotension among others.[1] It has the potential for seriousfood and drug interactions withsympathomimetic agents liketyramine that can result inhypertensive crisis.[1] Pargyline acts as anon-selective andirreversibleinhibitor of themonoamine oxidasesMAO-A andMAO-B.[6] The exactmechanism of thehypotensive effects of pargyline and other MAOIs is unclear.[9][10][11][12]Structurally, pargyline is abenzylaminederivative and is related toselegiline andclorgyline.[13][14][15]
Pargyline was first described in 1960[9][16][17] and was introduced for medical use in 1963.[18] It was available in theUnited States and theUnited Kingdom.[18][2][5] The clinical use of pargyline was limited due to its side effects and interactions.[1] The drug remained available in the United States as late as 2000.[5] However, it was fully discontinued worldwide by 2007.[19]
Pargyline is used as anantihypertensive agent in the treatment ofhypertension (high blood pressure).[1] The dosage was 12.5 to 200 mg per day.[1][12] Itsonset of action is slow and several weeks of continuous administration are required for the effects to develop fully upon initiation of treatment.[1][12] The decrease in blood pressure with pargyline is described as impressive and is especially strong when standing.[1][12] However, the blood pressure decrease with pargyline is often difficult to control adequately.[1]
Pargyline shares itsmechanism of action,monoamine oxidase inhibition, with a class ofantidepressants that includesphenelzine,tranylcypromine, andisocarboxazid, among others.[18][6][7] However, unlike other MAOIs, pargyline itself was never licensed for treatment ofdepression.[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".[18]
Orthostatic hypotension (excessively low blood pressure when standing or standing up) is a prominentside effect of pargyline.[1][12] Other side effects includedry mouth,dizziness,nausea,headaches,increased appetite,nervousness,insomnia,agitation,sedation,manic reactions, andpsychotic reactions.[8][12]
Pargyline has the potential for seriousfood and drug interactions due to its MAOI actions.[6] This includeshypertensive crisis with intake ofnorepinephrine releasing agents liketyramine,amphetamine, andephedrine.[6] Tyramine is found in high concentrations in certaincheeses and other foods and can result in hypertensive crisis often referred to as the "cheese reaction".[6] Episodes of hypertensive crisis can be severe or fatal and this has greatly limited the clinical use of pargyline.[6] Hypertensive crisis with pargyline is treatedintravenously withsympatholyticalpha blockers likephentolamine.[1]
Combination of pargyline and theantihypertensive agentmethyldopa has been found to result in intense and potentially fatalcentral nervous systemexcitation in rodents.[12][20][21][22][23] This has been said to resemble the effects ofamphetamineoverdose.[12][21][22] The interaction appears to be due to inhibition by pargyline of themetabolism of normally short-lived methyldopametabolites likeα-methyldopamine andα-methylnorepinephrine that act as potentcatecholamine releasing agents.[21][22]Visual hallucinations have been reported with coadministration of pargyline and methyldopa in humans.[24][20][23] As such, use of methyldopa in combination with pargyline and other MAOIs iscontraindicated.[24][12][20][21][22]
Pargyline is also adisulfiram-like drug andaldehyde dehydrogenase (ALDH) inhibitor similarly todisulfiram and can producealcohol intolerance-type reactions withalcohol.[3][25][12]
Pargyline is anon-selective andirreversiblemonoamine oxidase inhibitor (MAOI), or aninhibitor of themonoamine oxidase (MAO)enzyme.[6] This enzyme is involved in themetabolism of themonoamine neurotransmittersserotonin,norepinephrine, anddopamine.[6][26] Pargyline is said to have slight preference or selectivity for inhibition ofMAO-B overMAO-A (IC50Tooltip half-maximal inhibitory concentration = 8.20 nM and 11.52 nM, respectively).[6][27][28][29] Using rodent systems however, pargyline showed 2- to 356-fold selectivity for MAO-B inhibition over MAO-A inhibition in different studies (compared to 16- to 6401-fold selectivity with selegiline).[30] In relation to the preceding, pargyline has been referred to as a so-called semi-selective MAO-B inhibitor.[31][32] It has also been found to show some selectivity for MAO-B inhibition with a single dose but results in non-selective inhibition with continuous administration.[32]
Pargyline produces itsantihypertensive effects via MAO inhibition.[9][10] However, the exactmechanism of action by which this occurs is unclear.[9][10][11][12] Pargyline and other MAOIs inhibit the metabolism of norepinephrine and cause accumulation of norepinephrine in the heart, brain, and other adrenergic tissues.[9][10][11][12] Some possibilities include diminished responsiveness to norepinephrine via increased norepinephrine levels inblood vessels and blockade blockade of therelease of norepinephrine fromperipheralsympatheticneurons.[9][1][12] Another possibility is that pargyline increases levels offalse neurotransmitters likeoctopamine andtyramine, which are weakerpressor agents than norepinephrine.[9][10][1][33] However, the involvement of octopamine in the hypotensive effects of pargyline and other MAOIs is uncertain.[9][1][33] Yet another possibility is that the hypotensive effects may be due to accumulation ofN-acetylserotonin, which shows antihypertensive effects in animals.[9][34] As of 2018, the precise mechanism of the hypotensive effects of MAOIs still remains unresolved.[9]
In addition to its actions as an MAOI, pargyline has been found to bind with highaffinity to theI2 imidazoline receptor.[35] This receptor has been found to actually be anallosteric site on themonoamine oxidase (MAO)enzyme.[6][35]
A high dose of pargyline (10 mg/kg) has been found tostimulate locomotor activity, apsychostimulant-like effect, in certain behavioral tests in rats.[36][37] This might be due to its MAOI activity and increased dopamine levels in thenucleus accumbens or might be related to stimulant-like effects of itsmetabolites includingbenzylamine,N-methylbenzylamine, and/orN-propargylbenzylamine.[36][37] However, no studies on this matter have been conducted.[36][38] Certain other MAOIs, likeiproniazid,phenelzine,pheniprazine, andtranylcypromine, but notnialamide, have likewise been found to produceamphetamine- and psychostimulant-like effects at high doses in animals.[39] Several of these agents are known to metabolize intophenethylamines andamphetamines withcatecholamine-releasing activity[38][40] or to have intrinsic catecholamine-releasing actions of their own.[40][41][42] Benzylamine derivatives have been found to act ascatecholamine reuptake inhibitors.[43]
Pargyline has been found to act as an irreversiblealdehyde dehydrogenase (ALDH) inhibitor.[3][25] It is adisulfiram-like drug and can produceintolerance-type reactions withalcohol similarly todisulfiram.[3] The ALDH inhibition of pargyline appears to be mediated by itsmetabolites, namelypropiolaldehyde, but alsopropargylamine andbenzylamine.[3][25]
Pargyline has been found to act as areversible inhibitor ofdiamine oxidase (DAO)-mediatedputrescine metabolism.[25][44] It has additionally been found to act as a weak inhibitor ofarylalkyl acylamidase and ofhistamineN-methyltransferase.[25][45][46]
In contrast toselegiline, pargyline does not appear to showcatecholaminergic activity enhancer (CAE)-like effects.[31][32][47] Similarly, pargyline is not anagonist of the mouseTAAR1.[48]
Pargyline has highlipophilicity[49][26] and is predicted to cross theblood–brain barrier.[26] The drug has been shown to elevatebrain monoamine levels, for instance of serotonin norepinephrine, dopamine, andtrace amines, in animals.[50][51]
Pargyline isN-demethylated andN-depropargylated byCYP2E1 to formarylalkylamine and othermetabolites includingbenzylamine,N-methylbenzylamine, andN-propargylbenzylamine, among others.[27][3][52] These metabolites may then undergo additionalmetabolism, for instancehydroxylation andoxidation.[27][3][52] It also formspropiolaldehyde andpropargylamine.[3]N‐Propargylbenzylamine, which is a majoractive metabolite of pargyline, is apotent andselective inhibitor of MAO-Bin vivo in rats and may contribute importantly to MAO-B inhibition with pargyline.[27][50][52][53] Other metabolites, like propiolaldehyde, are potent ALDH inhibitors.[3]
Pargyline is aderivative ofbenzylamine and is also known asN-methyl-N-propargylbenzylamine.[13][49] It is used pharmaceutically as thehydrochloridesalt.[4][5][13]
Pargyline is alipophiliccompound, with a predictedlog P of about 2.1.[49][26]
Pargyline preceded and isstructurally related to theselective andirreversibleMAO-B inhibitorselegiline (deprenyl; (R)-(–)-N-methyl-N-propargylamphetamine).[14][15][54]Clorgyline (MB-9302;N-methyl-N-propargyl-3-(2,4-dichlorophenoxy)propylamine), another structural analogue of pargyline, is a selective and irreversibleMAO-A inhibitor.[55][56][57]
Pargyline was first described in thescientific literature in 1960.[9][16][17] It was brought to market in theUnited States and theUnited Kingdom byAbbott Laboratories in 1963 as anantihypertensive drug.[18] It was one of several MAOIs introduced in the 1960s includingnialamide,isocarboxazid,phenelzine, andtranylcypromine.[58][59][60][61] By 2007, the drug was discontinued.[19] As of 2014[update], there were nogeneric versions available in the United States.[2] It continued to be available in the United States as late as 2000.[5]
Pargyline is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, while itsUSANTooltip United States Adopted Name andBANMTooltip British Approved Name in the case of thehydrochloridesalt ispargyline hydrochloride.[4][5][13] The drug is also known by the developmental code nameMO-911.[26] Marketed brand names of pargyline have included Eutonyl and Eutron.[4][5][13]
Pargyline has been studied in the treatment ofdepression.[7][8][62][63][64][65][66][67]
{{cite book}}:|journal= ignored (help)Two more novel antihypertensives appeared in the advertising pages of the BMJ before the end of 1963. The first was pargyline, brand name Eutonyl, marketed by Abbott. The company had observed that this non-hydrazine MAO inhibitor had, in common with other MAO inhibitors, a hypotensive effect. The text suggested that the drug, when combined with their other drug Enduron (methyclothiazide), allowed a lowering of the dose of Eutonyl (BMJ, 12-10-63). The selling point of Eutonyl was 'lowers blood pressure, brightens emotional outlook'.
The administration of methyldopa to mice pretreated with the MAOI pargyline resulted in central nervous system excitation [van Rossum and Hurkmans, 1963]. Warning was then issued against the concomitant use of MAOIs and methyldopa in humans [van Rossum 1963]. A case of visual hallucinations was reported following the administration of methyldopa to a patient receiving pargyline [Paykel, 1966].
Pargyline was earlier considered to be a selective inhibitor of MAO-B. In an appropriate dose and after a single administration, pargyline shows some selectivity to MAO-B, but when it is given chronically it induces a non-selective inhibition of both enzyme types [38]. [...] selegiline, in contrast to pargyline and tranylcypromine, blocks the release of NA from the storage vesicles of the rat heart [7, 66]. [...] The effects of various MAO-B inhibitors on rabbit arterial strip response to T A were studied recently [Ill]. In addition to selegiline, MDL-72145, Ro 16-6491, AGN-1135, J-508, U-1424, TZ-650 were included in these studies. All of the MAO-B selective inhibitors except selegiline potentiated the effect of T A on the pulmonary artery strip, and similar results were also obtained in anesthetized cats and rats in vivo regarding blood pressure response to T A [ 112]. Tranylcypromine, pargyline, and clorgyline were also shown to be strong potentiators of TA both in vitro and in vivo. Selegiline was the only exception, which indicates that the lack ofT A potentiation is not a general characteristic of MAO-B inhibitors.
The MAO inhibitors are subdivided, not only according to structure (hydrazine or non-hydrazine) but also according to the presence or absence of inherent amphetamine-like activity. Thus high doses of iproniazid, pheniprazine, phenelzine and tranylcypromine directly increase motor activity, whereas nialamide and pargyline do not.
Pargyline is promoted only for the treatment of hypertension, and not for depression.