Pargyline: Difference between revisions

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Drugbox

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 414591272

| image = Pargyline.svg

| alt = Skeletal formula of pargyline

| width =

| image2 = Pargyline-3D-balls.png

| alt2 = Ball-and-stick model of the pargyline molecule

| width2 =

<!-- Clinical data -->

| tradename = Eutonyl; Eutron

| MedlinePlus = a682088

| pregnancy_category =

| legal_status =

| routes_of_administration = [[Oral administration|Oral]]<ref name="HayesSchneck1976">{{cite journal | vauthors = Hayes AH, Schneck DW | title = Antihypertensive pharmacotherapy | journal = Postgraduate Medicine | volume = 59 | issue = 5 | pages = 155–162 | date = May 1976 | pmid = 57611 | doi = 10.1080/00325481.1976.11714363 }}</ref><ref name="Drugs@FDA" />

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound =

| metabolism =

| metabolites = • ''N''-Methylbenzylamine<ref name="KoppakaThompsonChen2012" /><br />• ''N''-Propargylbenzylamine<ref name="KoppakaThompsonChen2012" /><br />• ''N''-Methylpropargylamine<ref name="KoppakaThompsonChen2012" /><br />• [[Benzylamine]]<ref name="KoppakaThompsonChen2012" /><br />• [[Propiolaldehyde]]<ref name="KoppakaThompsonChen2012" /><br />• [[Propargylamine]]<ref name="KoppakaThompsonChen2012" /><br />• [[Benzaldehyde]]<ref name="KoppakaThompsonChen2012" /><br />• Pargyline-''N''-oxide<ref name="KoppakaThompsonChen2012" />

| elimination_half-life =

| excretion =

<!-- Identifiers -->

| IUPHAR_ligand = 7262

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 555-57-7

| ATC_prefix = C02

| ATC_suffix = KC01

| ATC_supplemental = {{ATC|C02|LL01}}

| PubChem = 4688

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01626

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 673

| ChEBI_Ref =

| ChEBI = 7930

| synonyms = MO-911; A-19120; Lopac-P-8013; NSC-43798; ''N''-Methyl-''N''-propargylbenzylamine

<!-- Chemical data -->

| IUPAC_name = ''N''-benzyl-''N''-methylprop-2-yn-1-amine

| C=11 | H=13 | N=1

| SMILES = C#CCN(C)Cc1ccccc1

<!-- Definition and medical uses -->

'''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.<ref name="Elks2014">{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA934 | access-date=11 August 2024 | page=934}}</ref><ref name="IndexNominum2000">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum 2000: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2000 | isbn=978-3-88763-075-1 | url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA795 | access-date=2024-08-11 | page=795}}</ref><ref name="Finberg2014">{{cite journal | vauthors = Finberg JP | title = Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release | journal = Pharmacology & Therapeutics | volume = 143 | issue = 2 | pages = 133–152 | date = August 2014 | pmid = 24607445 | doi = 10.1016/j.pharmthera.2014.02.010 }}</ref> It has also been studied as an [[antidepressant]], but was never licensed for use in the treatment of [[depression (mood)|depression]].<ref name="KlineCooper1980" /><ref name="Murphy1977" /> The drug is taken [[oral administration|by mouth]].<ref name="HayesSchneck1976" /><ref name="Drugs@FDA" />

<!-- Side effects, mechanism of action, and chemistry -->

[[Side effect]]s of pargyline include [[orthostatic hypotension]] among others.<ref name="HayesSchneck1976" /> It has the potential for serious [[drug interaction|food and drug interaction]]s with [[sympathomimetic agent]]s like [[tyramine]] that can result in [[hypertensive crisis]].<ref name="HayesSchneck1976" /> Pargyline acts as a [[binding selectivity|non-selective]] and [[irreversible inhibitor|irreversible]] [[enzyme inhibitor|inhibitor]] of the [[monoamine oxidase]]s [[MAO-A]] and [[MAO-B]].<ref name="Finberg2014" /> The exact [[mechanism of action|mechanism]] of the [[hypotension|hypotensive]] effects of pargyline and other MAOIs is unclear.<ref name="Tipton2018" /><ref name="Abrams1969" /><ref name="McDonald1988" /><ref name="Mizgala1965" /> [[Chemical structure|Structurally]], pargyline is a [[benzylamine]] [[chemical derivative|derivative]] and is related to [[selegiline]] and [[clorgyline]].<ref name="MortonHall2012" /><ref name="FowlerOrelandCallingham1981" /><ref name="Miklya2014a" />

<!-- History, society, and culture -->

Pargyline was first described in 1960<ref name="Tipton2018" /><ref name="Ford1961" /><ref name="BryantTorosdagSchvartz1961" /> and was introduced for medical use in 1963.<ref name="GreenHaddadAronson2018" /> It was available in the [[United States]] and the [[United Kingdom]].<ref name="GreenHaddadAronson2018" /><ref name="Drugs@FDA" /><ref name="IndexNominum2000" /> The clinical use of pargyline was limited due to its side effects and interactions.<ref name="HayesSchneck1976" /> The drug remained available in the United States as late as 2000.<ref name="IndexNominum2000" /> However, it was fully discontinued worldwide by 2007.<ref name="Pray2007" />

==Medical uses==

Pargyline is used as an [[antihypertensive agent]] in the treatment of [[hypertension]] (high blood pressure).<ref name="HayesSchneck1976" /> The dosage was 12.5 to 200{{nbsp}}mg per day.<ref name="HayesSchneck1976" /><ref name="Mizgala1965">{{cite journal | vauthors = Mizgala HF | title = Newer Drugs in the Treatment of Hypertension | journal = Canadian Medical Association Journal | volume = 92 | issue = 17 | pages = 918–922 | date = April 1965 | pmid = 14289140 | pmc = 1928040 | doi = }}</ref> Its [[onset of action]] is slow and several weeks of continuous administration are required for the effects to develop fully upon initiation of treatment.<ref name="HayesSchneck1976" /><ref name="Mizgala1965" /> The decrease in blood pressure with pargyline is described as impressive and is especially strong when standing.<ref name="HayesSchneck1976" /><ref name="Mizgala1965" /> However, the blood pressure decrease with pargyline is often difficult to control adequately.<ref name="HayesSchneck1976" />

Pargyline shares its [[mechanism of action]], [[monoamine oxidase inhibitor|monoamine oxidase inhibition]], with a class of [[antidepressant]]s that includes [[phenelzine]], [[tranylcypromine]], and [[isocarboxazid]], among others.<ref name="GreenHaddadAronson2018" /><ref name="Finberg2014" /><ref name="KlineCooper1980" /> However, unlike other MAOIs, pargyline itself was never licensed for treatment of [[depression (mood)|depression]].<ref name="KlineCooper1980" /><ref name="IndexNominum2000" /> In any case, the drug was studied in the treatment of depression<ref name="KlineCooper1980" /><ref name="Murphy1977" /> and was advertised in the 1960s as an antihypertensive agent that also "brightens emotional outlook".<ref name="GreenHaddadAronson2018" />

==Side effects==

[[Orthostatic hypotension]] (excessively low blood pressure when standing or standing up) is a prominent [[side effect]] of pargyline.<ref name="HayesSchneck1976" /><ref name="Mizgala1965" /> Other side effects include [[dry mouth]], [[dizziness]], [[nausea]], [[headache]]s, [[increased appetite]], [[nervousness]], [[insomnia]], [[psychomotor agitation|agitation]], [[sedation]], [[mania|manic reaction]]s, and [[psychosis|psychotic reactions]].<ref name="Murphy1977">{{cite book | vauthors = Murphy DL | title=Advances in Pharmacology | chapter=The Behavioral Toxicity of Monoamine Oxidase-lnhibiting Antidepressants | publisher=Elsevier | volume=14 | date=1977 | isbn=978-0-12-032914-4 | doi=10.1016/s1054-3589(08)60185-4 | pages=71–105}}</ref><ref name="Mizgala1965" />

== Interactions ==

Pargyline has the potential for serious [[drug interaction|food and drug interaction]]s due to its MAOI actions.<ref name="Finberg2014" /> This includes [[hypertensive crisis]] with intake of [[norepinephrine releasing agent]]s like [[tyramine]], [[amphetamine]], and [[ephedrine]].<ref name="Finberg2014" /> Tyramine is found in high concentrations in certain [[cheese]]s and other foods and can result in hypertensive crisis often referred to as the "cheese reaction".<ref name="Finberg2014" /> Episodes of hypertensive crisis can be severe or fatal and this has greatly limited the clinical use of pargyline.<ref name="Finberg2014" /> Hypertensive crisis with pargyline is treated [[intravenous infusion|intravenously]] with [[sympatholytic]] [[alpha blocker]]s like [[phentolamine]].<ref name="HayesSchneck1976" />

Combination of pargyline and the [[antihypertensive agent]] [[methyldopa]] has been found to result in intense and potentially fatal [[central nervous system]] [[psychostimulant|excitation]] in rodents.<ref name="Mizgala1965" /><ref name="Ragheb1981">{{cite journal | vauthors = Ragheb M | title = Drug interactions in psychiatric practice | journal = International Pharmacopsychiatry | volume = 16 | issue = 2 | pages = 92–118 | date = 1981 | pmid = 6120917 | doi = 10.1159/000468482 | quote = 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]. }}</ref><ref name="VanRossumHurkmans1963">{{cite journal | vauthors = Hurkmans JA | title = Reversal of the effect of α-methyldopa by monoamine oxidase inhibitors | journal = The Journal of Pharmacy and Pharmacology | volume = 15 | issue = 1 | pages = 493–499 | date = August 1963 | pmid = 14059015 | doi = 10.1111/j.2042-7158.1963.tb12824.x }}</ref><ref name="vanRossum1963">{{cite journal | vauthors = van ROSSUM J | title = Potential dangers of monoamineoxidase inhibitors and alpha-methyldopa | journal = Lancet | volume = 1 | issue = 7287 | pages = 950–951 | date = April 1963 | pmid = 13975251 | doi = 10.1016/S0140-6736(63)91728-8 }}</ref><ref name="Paykel1966">{{cite journal | vauthors = Paykel ES | title = Hallucinosis on combined methyldopa and pargyline | journal = British Medical Journal | volume = 1 | issue = 5490 | pages = 803 | date = March 1966 | pmid = 5910115 | pmc = 1844519 | doi = 10.1136/bmj.1.5490.803-a }}</ref> This has been said to resemble the effects of [[amphetamine]] [[overdose]].<ref name="Mizgala1965" /><ref name="VanRossumHurkmans1963" /><ref name="vanRossum1963" /> The interaction appears to be due to inhibition by pargyline of the [[metabolism]] of normally short-lived methyldopa [[metabolite]]s like [[α-methyldopamine]] and [[α-methylnorepinephrine]] that act as potent [[catecholamine releasing agent]]s.<ref name="VanRossumHurkmans1963" /><ref name="vanRossum1963" /> [[Visual hallucination]]s have been reported with coadministration of pargyline and methyldopa in humans.<ref name="Hartshorn1974">{{cite journal | vauthors = Hartshorn EA | title=Interactions of CNS Drugs Psychotherapeutic Agents — Antidepressants | journal=Drug Intelligence & Clinical Pharmacy | volume=8 | issue=10 | date=1974 | issn=0012-6578 | doi=10.1177/106002807400801006 | pages=591–606}}</ref><ref name="Ragheb1981" /><ref name="Paykel1966" /> As such, use of methyldopa in combination with pargyline and other MAOIs is [[contraindication|contraindicated]].<ref name="Hartshorn1974" /><ref name="Mizgala1965" /><ref name="Ragheb1981" /><ref name="VanRossumHurkmans1963" /><ref name="vanRossum1963" />

Pargyline is also a [[disulfiram-like drug]] and [[aldehyde dehydrogenase]] (ALDH) inhibitor similarly to [[disulfiram]] and can produce [[alcohol intolerance]]-type reactions with [[alcohol (drug)|alcohol]].<ref name="KoppakaThompsonChen2012" /><ref name="Holt2004" /><ref name="Mizgala1965" />

==Pharmacology==

===Pharmacodynamics===

====Monoamine oxidase inhibition====

Pargyline is a [[binding selectivity|non-selective]] and [[irreversible inhibitor|irreversible]] [[monoamine oxidase inhibitor]] (MAOI), or an [[enzyme inhibitor|inhibitor]] of the [[monoamine oxidase]] (MAO) [[enzyme]].<ref name="Finberg2014" /> This enzyme is involved in the [[metabolism]] of the [[monoamine neurotransmitter]]s [[serotonin]], [[norepinephrine]], and [[dopamine]].<ref name="Finberg2014" /><ref name="DrugBank">{{cite web | title=Pargyline: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=29 August 2007 | url=https://go.drugbank.com/drugs/DB01626 | access-date=11 August 2024}}</ref> Pargyline is said to have slight preference or selectivity for inhibition of [[MAO-B]] over [[MAO-A]] ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} = 8.20{{nbsp}}nM and 11.52{{nbsp}}nM, respectively).<ref name="Finberg2014" /><ref name="YamadaYasuhara2004" /><ref name="FisarHroudováRaboch2010">{{cite journal | vauthors = Fisar Z, Hroudová J, Raboch J | title = Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers | journal = Neuro Endocrinology Letters | volume = 31 | issue = 5 | pages = 645–656 | year = 2010 | pmid = 21200377 }}</ref><ref name="MurphyKaroumPickar1998">{{Cite book |title=MAO — the Mother of all Amine Oxidases |vauthors=Murphy DL, Karoum F, Pickar D, etal |year=1998 |isbn=978-3-211-83037-6 | veditors = Finberg JP, Youdim MB, Riederer P, Tipton KF |series=Journal of Neural Transmission Supplementum |volume=52 |pages=39–48 |chapter=Differential trace amine alterations in individuals receiving acetylenic inhibitors of MAO-A (Clorgyline) or MAO-B (Selegiline and pargyline) |doi=10.1007/978-3-7091-6499-0_5 |pmid=9564606 }}</ref> 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).<ref name="SzelenyiPaul1993">{{cite book | vauthors=Paul W, Szelenyi I | veditors = Szelenyi I | title=Inhibitors of Monoamine Oxidase B: Pharmacology and Clinical Use in Neurodegenerative Disorders | series=Milestones in Drug Therapy | chapter=Appendix I: Chemical Structures and Pharmacological Features of MAO-B Inhibitors | publisher=Birkhäuser Basel | publication-place=Basel | year=1993 | isbn=978-3-0348-6349-0 | issn=2296-6056 | pages=339–358}}</ref> In relation to the preceding, pargyline has been referred to as a so-called semi-selective MAO-B inhibitor.<ref name="Knoll1983">{{cite journal | vauthors = Knoll J | title = Deprenyl (selegiline): the history of its development and pharmacological action | journal = Acta Neurol Scand Suppl | volume = 95 | issue = | pages = 57–80 | date = 1983 | pmid = 6428148 | doi = 10.1111/j.1600-0404.1983.tb01517.x | url = | doi-access = free }}</ref><ref name="Magyar1993">{{cite book | last=Magyar | first=K. | title=Milestones in Drug Therapy | chapter=Pharmacology of Monoamine Oxidase Type B Inhibitors | publisher=Birkhäuser Basel | publication-place=Basel | year=1993 | isbn=978-3-0348-6349-0 | issn=2296-6056 | doi=10.1007/978-3-0348-6348-3_6 | language=de | page=125–143 | quote=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.}}</ref> 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.<ref name="Magyar1993" />

Pargyline produces its [[antihypertensive agent|antihypertensive]] effects via MAO inhibition.<ref name="Tipton2018" /><ref name="Abrams1969">{{cite journal | vauthors = Abrams WB | title = The mechanisms of action of antihypertensive drugs | journal = Diseases of the Chest | volume = 55 | issue = 2 | pages = 148–159 | date = February 1969 | pmid = 4887212 | doi = 10.1378/chest.55.2.148 }}</ref> However, the exact [[mechanism of action]] by which this occurs is unclear.<ref name="Tipton2018" /><ref name="Abrams1969" /><ref name="McDonald1988" /><ref name="Mizgala1965" /> Pargyline and other MAOIs inhibit the metabolism of norepinephrine and cause accumulation of norepinephrine in the heart, brain, and other adrenergic tissues.<ref name="Tipton2018" /><ref name="Abrams1969" /><ref name="McDonald1988">{{cite journal | vauthors = McDonald RH | title = The evolution of current hypertension therapy | journal = The American Journal of Medicine | volume = 85 | issue = 3B | pages = 14–18 | date = September 1988 | pmid = 3048093 | doi = 10.1016/0002-9343(88)90344-0 }}</ref><ref name="Mizgala1965" /> Some possibilities include diminished responsiveness to norepinephrine via increased norepinephrine levels in [[blood vessel]]s and blockade blockade of the [[neurotransmitter release|release]] of norepinephrine from [[peripheral nervous system|peripheral]] [[sympathetic nervous system|sympathetic]] [[neuron]]s.<ref name="Tipton2018" /><ref name="HayesSchneck1976" /><ref name="Mizgala1965" /> Another possibility is that pargyline increases levels of [[false neurotransmitter]]s like [[octopamine]] and [[tyramine]], which are weaker [[vasopressor|pressor agent]]s than norepinephrine.<ref name="Tipton2018" /><ref name="Abrams1969" /><ref name="HayesSchneck1976" /><ref name="Hicks1977">{{cite journal | vauthors = Hicks TP | title = The possible role of octopamine as a synaptic transmitter: a review | journal = Canadian Journal of Physiology and Pharmacology | volume = 55 | issue = 2 | pages = 137–152 | date = April 1977 | pmid = 17454 | doi = 10.1139/y77-022 }}</ref> However, the involvement of octopamine in the hypotensive effects of pargyline and other MAOIs is uncertain.<ref name="Tipton2018" /><ref name="HayesSchneck1976" /><ref name="Hicks1977" /> Yet another possibility is that the hypotensive effects may be due to accumulation of [[N-acetylserotonin|''N''-acetylserotonin]], which shows antihypertensive effects in animals.<ref name="Tipton2018" /><ref name="Oxenkrug1999">{{cite journal | vauthors = Oxenkrug GF | title = Antidepressive and antihypertensive effects of MAO-A inhibition: role of N-acetylserotonin. A review | journal = Neurobiology | volume = 7 | issue = 2 | pages = 213–224 | date = 1999 | pmid = 10591054 | doi = }}</ref> As of 2018, the precise mechanism of the hypotensive effects of MAOIs still remains unresolved.<ref name="Tipton2018" />

====Other actions====

In addition to its actions as an MAOI, pargyline has been found to bind with high [[affinity (pharmacology)|affinity]] to the [[imidazoline receptor|I₂ imidazoline receptor]].<ref name="PiletzHalarisErsnberger1995">{{cite journal | vauthors = Piletz JE, Halaris A, Ernsberger PR | title = Psychopharmacology of imidazoline and α₂-adrenergic receptors: implications for depression | journal = Critical Reviews in Neurobiology | volume = 9 | issue = 1 | pages = 29–66 (43) | year = 1995 | pmid = 8828003 | url = https://books.google.com/books?id=EP9FAQAAIAAJ&q=Pargyline | publisher = CRC Press }}</ref> This receptor has been found to actually be an [[allosteric site]] on the [[monoamine oxidase]] (MAO) [[enzyme]].<ref name="Finberg2014" /><ref name="PiletzHalarisErsnberger1995" />

A high dose of pargyline (10{{nbsp}}mg/kg) has been found to [[hyperlocomotion|stimulate locomotor activity]], a [[psychostimulant]]-like effect, in certain behavioral tests in rats.<ref name="KitanakaKitanakaTakemura2006">{{cite journal | vauthors = Kitanaka J, Kitanaka N, Takemura M | title = Modification of Monoaminergic Activity by MAO Inhibitors Influences Methamphetamine Actions | journal = Drug Target Insights | volume = 1 | issue = | pages = 19–28 | date = 2006 | pmid = 21901055 | pmc = 3155216 | doi = 10.1177/117739280600100001}}</ref><ref name="BarbelivienNymanHaapalinna2001">{{cite journal | vauthors = Barbelivien A, Nyman L, Haapalinna A, Sirviö J | title = Inhibition of MAO-A activity enhances behavioural activity of rats assessed using water maze and open arena tasks | journal = Pharmacology & Toxicology | volume = 88 | issue = 6 | pages = 304–312 | date = June 2001 | pmid = 11453370 | doi = 10.1034/j.1600-0773.2001.880604.x}}</ref> 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 [[metabolite]]s including [[benzylamine]], ''N''-methylbenzylamine, and/or ''N''-propargylbenzylamine.<ref name="KitanakaKitanakaTakemura2006" /><ref name="BarbelivienNymanHaapalinna2001" /> However, no studies on this matter have been conducted.<ref name="KitanakaKitanakaTakemura2006" /><ref name="BakerCoutts1989">{{cite journal | vauthors = Baker GB, Coutts RT | title = Metabolism of monoamine oxidase inhibitors | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 13 | issue = 3–4 | pages = 395–403 | date = 1989 | pmid = 2664891 | doi = 10.1016/0278-5846(89)90128-0 }}</ref> 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.<ref name="Spencer1977">{{cite journal | vauthors = Spencer PS | title = Review of the pharmacology of existing antidepressants | journal = British Journal of Clinical Pharmacology | volume = 4 | issue = Suppl 2 | pages = 57S–68S | date = 1977 | pmid = 334231 | pmc = 1429129 | doi = 10.1111/j.1365-2125.1977.tb05761.x | quote = 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. }}</ref> Several of these agents are known to metabolize into [[substituted phenethylamine|phenethylamine]]s and [[substituted amphetamine|amphetamine]]s with [[catecholamine releasing agent|catecholamine-releasing activity]]<ref name="BakerCoutts1989" /><ref name="BakerCouttsMcKenna1992">{{cite journal | vauthors = Baker GB, Coutts RT, McKenna KF, Sherry-McKenna RL | title = Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review | journal = Journal of Psychiatry & Neuroscience | volume = 17 | issue = 5 | pages = 206–214 | date = November 1992 | pmid = 1362653 | pmc = 1188458 | doi = }}</ref> or to have intrinsic catecholamine-releasing actions of their own.<ref name="BakerCouttsMcKenna1992" /><ref name="UlrichRickenAdli2017">{{cite journal | vauthors = Ulrich S, Ricken R, Adli M | title = Tranylcypromine in mind (Part I): Review of pharmacology | journal = European Neuropsychopharmacology | volume = 27 | issue = 8 | pages = 697–713 | date = August 2017 | pmid = 28655495 | doi = 10.1016/j.euroneuro.2017.05.007 | s2cid = 4913721 | doi-access = free }}</ref><ref name="RickenUlrichSchlattmann2017">{{cite journal | vauthors = Ricken R, Ulrich S, Schlattmann P, Adli M | title = Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression | journal = European Neuropsychopharmacology | volume = 27 | issue = 8 | pages = 714–731 | date = August 2017 | pmid = 28579071 | doi = 10.1016/j.euroneuro.2017.04.003 | s2cid = 30987747 | doi-access = free }}</ref> Benzylamine derivatives have been found to act as [[catecholamine reuptake inhibitor]]s.<ref name="KammererAmiriCho1979">{{cite journal | vauthors = Kammerer RC, Amiri B, Cho AK | title = Inhibition of uptake of catecholamines by benzylamine derivatives | journal = Journal of Medicinal Chemistry | volume = 22 | issue = 4 | pages = 352–355 | date = April 1979 | pmid = 430475 | doi = 10.1021/jm00190a004 }}</ref>

Pargyline has been found to act as an irreversible [[aldehyde dehydrogenase]] (ALDH) inhibitor.<ref name="KoppakaThompsonChen2012">{{cite journal | vauthors = Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V | title = Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application | journal = Pharmacological Reviews | volume = 64 | issue = 3 | pages = 520–539 | date = July 2012 | pmid = 22544865 | pmc = 3400832 | doi = 10.1124/pr.111.005538 }}</ref><ref name="Holt2004" /> It is a [[disulfiram-like drug]] and can produce [[alcohol intolerance|intolerance-type reaction]]s with [[alcohol (drug)|alcohol]] similarly to [[disulfiram]].<ref name="KoppakaThompsonChen2012" /> The ALDH inhibition of pargyline appears to be mediated by its [[metabolite]]s, namely [[propiolaldehyde]], but also [[propargylamine]] and [[benzylamine]].<ref name="KoppakaThompsonChen2012" /><ref name="Holt2004" />

Pargyline has been found to act as a [[reversible inhibitor]] of [[diamine oxidase]] (DAO)-mediated [[putrescine]] metabolism.<ref name="Holt2004">{{cite journal | vauthors = Holt A, Berry MD, Boulton AA | title = On the binding of monoamine oxidase inhibitors to some sites distinct from the MAO active site, and effects thereby elicited | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 251–266 | date = January 2004 | pmid = 14697900 | doi = 10.1016/S0161-813X(03)00104-9 | bibcode = 2004NeuTx..25..251H }}</ref><ref name="SourkesMissala1977">{{cite journal | vauthors = Sourkes TL, Missala K | title = Action of inhibitors on monoamine and diamine metabolism in the rat | journal = Canadian Journal of Biochemistry | volume = 55 | issue = 1 | pages = 56–59 | date = January 1977 | pmid = 402175 | doi = 10.1139/o77-010 }}</ref> It has additionally been found to act as a weak inhibitor of [[arylalkyl acylamidase]] and of [[histamine N-methyltransferase|histamine ''N''-methyltransferase]].<ref name="Holt2004" /><ref name="Hsu1984">{{cite journal | vauthors = Hsu LL | title = Pineal aryl acylamidase: effects of melatonin, serotonin-related compounds, beta-carbolines, RO4-4602 and antidepressants | journal = Research Communications in Chemical Pathology and Pharmacology | volume = 43 | issue = 2 | pages = 223–234 | date = February 1984 | pmid = 6709961 | doi = }}</ref><ref name="Boudíková-GirardScottWeinshilboum1993">{{cite journal | vauthors = Boudíková-Girard B, Scott MC, Weinshilboum R | title = Histamine N-methyltransferase: inhibition by monoamine oxidase inhibitors | journal = Agents and Actions | volume = 40 | issue = 1–2 | pages = 1–10 | date = September 1993 | pmid = 8147263 | doi = 10.1007/BF01976745 }}</ref>

In contrast to [[selegiline]], pargyline does not appear to show [[catecholaminergic activity enhancer]] (CAE)-like effects.<ref name="Knoll1983" /><ref name="Magyar1993" /><ref name="YenDallóKnoll1982">{{cite journal | vauthors = Yen TT, Dalló J, Knoll J | title = The aphrodisiac effect of low doses of (-) deprenyl in male rats | journal = Pol J Pharmacol Pharm | volume = 34 | issue = 5-6 | pages = 303–308 | date = 1982 | pmid = 6821215 | doi = | url = }}</ref> Similarly, pargyline is not an [[agonist]] of the mouse [[TAAR1]].<ref name="WolinskySwansonSmith2007">{{cite journal | vauthors = Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP | title = The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia | journal = Genes Brain Behav | volume = 6 | issue = 7 | pages = 628–639 | date = October 2007 | pmid = 17212650 | doi = 10.1111/j.1601-183X.2006.00292.x | url = }}</ref>

===Pharmacokinetics===

Pargyline has high [[lipophilicity]]<ref name="PubChem" /><ref name="DrugBank" /> and is predicted to cross the [[blood–brain barrier]].<ref name="DrugBank" /> The drug has been shown to elevate [[brain]] monoamine levels, for instance of serotonin norepinephrine, dopamine, and [[trace amine]]s, in animals.<ref name="Karoum1985" /><ref name="SpectorHirschBrodie1963">{{cite journal | vauthors = Spector S, Hirsch C, Brodie B | title=Association of behavoural effects of pargyline, a non-hydrazide mao inhibitor with increase in brain norepinephrine | journal=International Journal of Neuropharmacology | volume=2 | issue=1–2 | date=1963 | doi=10.1016/0028-3908(63)90037-6 | pages=81–93}}</ref>

Pargyline is ''N''-[[demethylation|demethylated]] and ''N''-[[dealkylation|depropargylated]] by [[CYP2E1]] to form [[arylalkylamine]] and other [[metabolite]]s including [[benzylamine]], ''N''-methylbenzylamine, and ''N''-propargylbenzylamine, among others.<ref name="YamadaYasuhara2004">{{cite journal | vauthors = Yamada M, Yasuhara H | title = Clinical pharmacology of MAO inhibitors: safety and future | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 215–221 | date = January 2004 | pmid = 14697896 | doi = 10.1016/S0161-813X(03)00097-4 | bibcode = 2004NeuTx..25..215Y }}</ref><ref name="KoppakaThompsonChen2012" /><ref name="BakerUrichukMcKenna1999">{{cite journal | vauthors = Baker GB, Urichuk LJ, McKenna KF, Kennedy SH | title = Metabolism of monoamine oxidase inhibitors | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 3 | pages = 411–426 | date = June 1999 | pmid = 10319194 | doi = 10.1023/a:1006901900106 }}</ref> These metabolites may then undergo additional [[drug metabolism|metabolism]], for instance [[hydroxylation]] and [[oxidation]].<ref name="YamadaYasuhara2004" /><ref name="KoppakaThompsonChen2012" /><ref name="BakerUrichukMcKenna1999" /> It also forms [[propiolaldehyde]] and [[propargylamine]].<ref name="KoppakaThompsonChen2012" /> ''N''‐Propargylbenzylamine, which is a major [[active metabolite]] of pargyline, is a [[potency (pharmacology)|potent]] and [[binding selectivity|selective]] inhibitor of MAO-B ''[[in vivo]]'' in rats and may contribute importantly to MAO-B inhibition with pargyline.<ref name="YamadaYasuhara2004" /><ref name="Karoum1985">{{cite book | vauthors = Karoum F | title=Neuropsychopharmacology of the Trace Amines | chapter=The Effects of Pargyline, Clorgyline, Deprenyl and their Metabolites on Rat Peripheral and Central Biogenic Amines: A Comparison between Changes in Urine Excretion and Brain Concentrations | publisher=Humana Press | publication-place=Totowa, NJ | date=1985 | isbn=978-1-4612-9397-2 | doi=10.1007/978-1-4612-5010-4_30 | pages=285–293}}</ref><ref name="BakerUrichukMcKenna1999" /><ref name="Karoum1987">{{cite journal | vauthors = Karoum F | title = N-propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl | journal = British Journal of Pharmacology | volume = 90 | issue = 2 | pages = 335–345 | date = February 1987 | pmid = 3103805 | pmc = 1916954 | doi = 10.1111/j.1476-5381.1987.tb08963.x }}</ref> Other metabolites, like propiolaldehyde, are potent ALDH inhibitors.<ref name="KoppakaThompsonChen2012" />

==Chemistry==

Pargyline is an [[chemical derivative|derivative]] of [[benzylamine]] and is also known as ''N''-methyl-''N''-propargylbenzylamine.<ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA215 | access-date=11 August 2024 | page=215}}</ref><ref name="PubChem">{{cite web | title=Pargyline | work = PubChem | publisher = U.S. National Library of Medicine | url=https://pubchem.ncbi.nlm.nih.gov/compound/4688 | access-date=11 August 2024}}</ref> It is used pharmaceutically as the [[hydrochloride]] [[salt (chemistry)|salt]].<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" />

Pargyline is a [[lipophilic]] [[chemical compound|compound]], with a predicted [[partition coefficient|log P]] of about 2.1.<ref name="PubChem" /><ref name="DrugBank" />

Pargyline preceded and is [[structural analog|structurally related]] to the [[binding selectivity|selective]] and [[irreversible inhibitor|irreversible]] [[MAO-B inhibitor]] [[selegiline]] (deprenyl; (''R'')-(–)-''N''-methyl-''N''-propargylamphetamine).<ref name="FowlerOrelandCallingham1981">{{cite journal | vauthors = Fowler CJ, Oreland L, Callingham BA | title = The acetylenic monoamine oxidase inhibitors clorgyline, deprenyl, pargyline and J-508: their properties and applications | journal = The Journal of Pharmacy and Pharmacology | volume = 33 | issue = 6 | pages = 341–347 | date = June 1981 | pmid = 6115003 | doi = 10.1111/j.2042-7158.1981.tb13800.x }}</ref><ref name="Miklya2014a">{{cite web|title = The History of Selegiline/(-)-Deprenyl the First Selective Inhibitor of B-Type Monoamine Oxidase and The First Synthetic Catecholaminergic Activity Enhancer Substance|url = http://inhn.org/archives/miklya-collection/the-history-of-selegiline-deprenyl-the-first-selective-inhibitor-of-b-type-monoamine-oxidase-and-the-first-synthetic-catecholaminergic-activity-enhancer-substance.html|website = International Network for the History of Neuropsychopharmacology|access-date = January 7, 2016|vauthors = Miklya I|date = March 13, 2014|archive-date = February 7, 2016|archive-url = https://web.archive.org/web/20160207154819/http://inhn.org/archives/miklya-collection/the-history-of-selegiline-deprenyl-the-first-selective-inhibitor-of-b-type-monoamine-oxidase-and-the-first-synthetic-catecholaminergic-activity-enhancer-substance.html|url-status = dead}}</ref><ref name="PubChem-Selegiline">{{cite web | title=Selegiline | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/26757 | access-date=18 July 2024}}</ref> [[Clorgyline]] (MB-9302; ''N''-methyl-''N''-propargyl-3-(2,4-dichlorophenoxy)propylamine), another structural analogue of pargyline, is a selective and irreversible [[MAO-A inhibitor]].<ref name="HallLoganParsons1969a">{{cite journal | vauthors = Hall DW, Logan BW, Parsons GH | title = Further studies on the inhibition of monoamine oxidase by M and B 9302 (clorgyline). I. Substrate specificity in various mammalian species | journal = Biochemical Pharmacology | volume = 18 | issue = 6 | pages = 1447–1454 | date = June 1969 | pmid = 5799116 | doi = 10.1016/0006-2952(69)90258-5 }}</ref><ref name="HallLogan1969">{{cite journal | vauthors = Hall DW, Logan BW | title = Further studies on the inhibition of monoamine oxidase by M & B 9302 (clorgyline). II. Comparison of M & B 9302 inhibition with that of iproniazid | journal = Biochemical Pharmacology | volume = 18 | issue = 8 | pages = 1955–1959 | date = August 1969 | pmid = 5811628 | doi = 10.1016/0006-2952(69)90291-3 }}</ref><ref name="HallLoganParsons1969b">{{cite journal | vauthors = Hall DW, Logan BW, Parsons GH | title = Inhibition of MAO by MB 9320 (clorgyline) substrate specificity in various mammalian species | date = 1969 | journal = Biochem. Pharmacol. | volume = 18 | issue = 6 | pages = 1447–1454 | doi = 10.1016/0006-2952(69)90258-5 | pmid = 5799116 | url = https://scholar.google.com/scholar?cluster=8374616370598318173}}</ref>

==History==

Pargyline was first described in the [[scientific literature]] in 1960.<ref name="Tipton2018">{{cite journal | vauthors = Tipton KF | title = 90 years of monoamine oxidase: some progress and some confusion | journal = Journal of Neural Transmission | volume = 125 | issue = 11 | pages = 1519–1551 | date = November 2018 | pmid = 29637260 | doi = 10.1007/s00702-018-1881-5 }}</ref><ref name="Ford1961">{{cite journal | vauthors = Ford RV | title = Clinical and pharmacologic observations on a monoamine oxidase inhibitor (pargyline hydrochloride) in hypertension | journal = Current Therapeutic Research, Clinical and Experimental | volume = 3 | issue = | pages = 378–382 | date = September 1961 | pmid = 13700727 | doi = }}</ref><ref name="BryantTorosdagSchvartz1961">{{cite journal | vauthors = Bryant JM, Torosdag S, Schvartz N, Fletcher L, Fertig H, Schwartz MS, Quan RB | title = Antihypertensive properties of pargyline hydrochloride. New non-hydrazine monoamine oxidase inhibitor compared with sulphonamide diuretics | journal = JAMA | volume = 178 | issue = | pages = 406–409 | date = October 1961 | pmid = 13874134 | doi = 10.1001/jama.1961.73040430005010 }}</ref> It was brought to market in the [[United States]] and the [[United Kingdom]] by [[Abbott Laboratories]] in 1963 as an [[Antihypertensive drug|antihypertensive]] drug.<ref name="GreenHaddadAronson2018">{{cite journal | vauthors = Green AR, Haddad PM, Aronson JK | title = Marketing medicines: charting the rise of modern therapeutics through a systematic review of adverts in UK medical journals (1950-1980) | journal = British Journal of Clinical Pharmacology | volume = 84 | issue = 8 | pages = 1668–1685 | date = August 2018 | pmid = 29442380 | pmc = 6046508 | doi = 10.1111/bcp.13549 | quote = 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'. }}</ref> It was one of several MAOIs introduced in the 1960s including [[nialamide]], [[isocarboxazid]], [[phenelzine]], and [[tranylcypromine]].<ref name="Shorter2005">{{Cite book | vauthors = Shorter E |title=A Historical Dictionary of Psychiatry |publisher=Oxford University Press |year=2005 |isbn=0195176685 |page=146}}</ref><ref name="WardellLasagna1975">{{Cite book | vauthors = Wardell WM, Lasagna L |title=Regulation Drug Development |publisher=American Enterprise Institute |year=1975 |isbn=0844731676 |series=Evaluative Studies |volume=21 |page=60}}</ref><ref name="CouncilOnDrugs1963">{{Cite journal | author = ((Council on Drugs' Statements)) |year=1963 |title=New Drugs and Developments in Therapeutics: Pargyline Hydrochloride (Eutonyl) |url=http://jama.jamanetwork.com/article.aspx?articleid=665676 |journal=JAMA |volume=184 |issue=11 |page=887 |doi=10.1001/jama.1963.03700240079013}}</ref><ref name="DrugsTherapeuticsBulletin1963">{{Cite journal |date=15 November 1963 |title=Eutonyl and MAO inhibitors |url=http://dtb.bmj.com/content/1/15/59 |journal=Drug and Therapeutics Bulletin |language=en |volume=1 |issue=15 |pages=59–60 |doi=10.1136/dtb.1.15.59 |issn=1755-5248 |s2cid=220162992 |quote=Pargyline is promoted only for the treatment of hypertension, and not for depression.}}</ref> By 2007, the drug was discontinued.<ref name="Pray2007">{{Cite journal | vauthors = Pray WS |year=2007 |title=Interactions Between Nonprescription Products and Psychotropic Medications |url=http://www.medscape.com/viewarticle/566743_2 |journal=US Pharmacist |volume=32 |issue=11 |pages=12–15}}</ref> {{As of|2014|lc=n}}, there were no [[generic drug|generic versions]] available in the United States.<ref name="Drugs@FDA">{{Cite web |title=Eutonyl | work = Drugs@FDA Database |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=EUTONYL |access-date=July 19, 2014 | publisher = U.S. Food and Drug Administration (FDA) }}</ref> It continued to be available in the United States as late as 2000.<ref name="IndexNominum2000" />

==Society and culture==

===Names===

''Pargyline'' is the [[generic term|generic name]] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}, while its {{Abbrlink|USAN|United States Adopted Name}} and {{Abbrlink|BANM|British Approved Name}} in the case of the [[hydrochloride]] [[salt (chemistry)|salt]] is ''pargyline hydrochloride''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /> The drug is also known by the developmental code name ''MO-911''.<ref name="DrugBank" /> Marketed brand names of pargyline have included Eutonyl and Eutron.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" />

==Research==

Pargyline has been studied in the treatment of [[depression (mood)|depression]].<ref name="KlineCooper1980">{{cite book | vauthors = Kline NS, Cooper TB | title=Psychotropic Agents | chapter=Monoamine Oxidase Inhibitors as Antidepressants | series=Handbook of Experimental Pharmacology | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | volume=55 / 1 | date=1980 | isbn=978-3-642-67540-9 | doi=10.1007/978-3-642-67538-6_17 | pages=369–397}}</ref><ref name="Murphy1977" /><ref name="BucciHendersonSaunders1962">{{cite journal | vauthors = Bucci L, Henderson CT, Saunders JC | title = Pargyline, a paragon of affective therapy | journal = Psychosomatics | volume = 3 | issue = 4| pages = 308–311 | date = 1962 | pmid = 13874209 | doi = 10.1016/s0033-3182(62)72680-0 }}</ref><ref name="OltmanFriedman1963">{{cite journal | vauthors = Oltman JE, Friedman S | title = Pargyline in the Treatment of Depressive Illnesses | journal = The American Journal of Psychiatry | volume = 120 | issue = 5| pages = 493–494 | date = November 1963 | pmid = 14054108 | doi = 10.1176/ajp.120.5.493 }}</ref><ref name="Saunders1963">{{cite journal | vauthors = Saunders JC | title = Treatment of hospitalized depressed and schizophrenic patients with monoamine oxidase inhibitors: including reflections on pargyline | journal = Annals of the New York Academy of Sciences | volume = 107 | issue = 3| pages = 1081–1089 | date = July 1963 | pmid = 13986821 | doi = 10.1111/j.1749-6632.1963.tb13351.x | bibcode = 1963NYASA.107.1081S }}</ref><ref name="JanecekSchieleVestre1963">{{cite journal | vauthors = Janecek J, Schiele BC, Vestre ND | title = Pargyline and Tranylcypromine in the Treatment of Hospitalized Depressed Patients | journal = The Journal of New Drugs | volume = 3 | issue = 5 | pages = 309–316 | date = 1963 | pmid = 14089807 | doi = 10.1002/j.1552-4604.1963.tb00084.x }}</ref><ref name="Stern1963">{{cite journal | vauthors = Stern FH | title = Pargyvine hydrochloride: a new agent for the control of hypertension and mental depression | journal = Journal of the American Geriatrics Society | volume = 11 | issue = 7| pages = 670–672 | date = July 1963 | pmid = 13983943 | doi = 10.1111/j.1532-5415.1963.tb02616.x }}</ref><ref name="Ayd1965">{{cite journal | vauthors = Ayd FJ | title = A clinical evaluation of pargyline hydrochloride (Eutonyl) in the management of mental depression | journal = International Journal of Neuropsychiatry | volume = 1 | issue = | pages = 233–238 | date = 1965 | pmid = 14309088 | doi = }}</ref>

== References ==

{{Reflist}}

{{Antihypertensives and diuretics}}

{{Monoamine metabolism modulators}}

[[Category:Acetaldehyde dehydrogenase inhibitors]]

[[Category:Amines]]

[[Category:Antihypertensive agents]]

[[Category:Benzyl compounds]]

[[Category:Disulfiram-like drugs]]

[[Category:Monoamine oxidase inhibitors]]

[[Category:Propargyl compounds]]

[[Category:Withdrawn drugs]]