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Monoamine reuptake inhibitor

Drug class

Monoamine reuptake inhibitor
Summary

Drug class

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

Uses

The majority of currently approved antidepressants act predominantly or exclusively as MRIs, including the selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and almost all of the tricyclic antidepressants (TCAs). Many psychostimulants used either in the treatment of or as appetite suppressants in the treatment of obesity also behave as MRIs, although notably amphetamine (and methamphetamine), which do act to some extent as monoamine reuptake inhibitors, exerts their effects primarily as releasing agents. Additionally, psychostimulants acting as MRIs that affect dopamine such as cocaine and methylphenidate are often abused as recreational drugs. As a result, many of them have become controlled substances, which in turn has resulted in the clandestine synthesis of a vast array of designer drugs for the purpose of bypassing drug laws; a prime example of such is the mixed monoamine reuptake inhibitor and releasing agent mephedrone.

Types of MRIs

There are a variety of different kinds of MRIs, of which include the following:

  • Specific for one monoamine transporter
    • Serotonin reuptake inhibitor (SRI)
      • Selective serotonin reuptake inhibitor (SSRI)
    • Norepinephrine reuptake inhibitor (NRI)
      • Selective norepinephrine reuptake inhibitor (sNRI)
    • Dopamine reuptake inhibitor (DRI)
  • Non-specific, binding to two or more monoamine transporters
    • Serotonin–norepinephrine reuptake inhibitor (SNRI)
    • Serotonin–dopamine reuptake inhibitor (SDRI)
    • Norepinephrine–dopamine reuptake inhibitor (NDRI)
    • Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)

Binding profiles

CompoundTypeClass
3-Methylmethcathinone450080
Amfonelic acidNDND
vauthors = Ceci A, Garattini S, Gobbi M, Mennini Ttitle = Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brainjournal = Br. J. Pharmacol.volume = 88issue = 1pages = 269–75year = 1986pmid = 3708219pmc = 1917102doi = 10.1111/j.1476-5381.1986.tb09495.x}}100,000 (rat)10,000 (rat)
Amitriptyline4.3035
Amoxapine5816.0
Amphetamine100,000ND
D-Amphetamine100,000530
L-Amphetamine100,000ND
Atomoxetine775
Bupropion9,10052,000
Butriptyline1,3605,100
Chlorphenamine15.21,440
Citalopram1.164,070
vauthors = Owens JM, Knight DL, Nemeroff CBtitle = [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]language = frjournal = Encephalevolume = 28issue = 4pages = 350–5year = 2002pmid = 12232544 }}1.17,841
Clomipramine0.2838
vauthors = Rothman RB, Baumann MHtitle = Monoamine transporters and psychostimulant drugsjournal = Eur. J. Pharmacol.volume = 479issue = 1–3pages = 23–40year = 2003pmid = 14612135doi = 10.1016/j.ejphar.2003.08.054}}3,87810,000
Cocaine304779
title=EMCDDA–Europol Joint Report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP)website=www.euda.europa.euurl=https://www.euda.europa.eu/publications/joint-reports/alpha-pvp_enaccess-date=2024-07-16}}313±17 (IC50)292±34 (IC50)
Desipramine17.60.83
Desmethylcitalopram3.61,820
Desmethylsertraline3.0390
vauthors = Nisoli E, Carruba MOtitle = An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of actionjournal = Obes Revvolume = 1issue = 2pages = 127–39year = 2000pmid = 12119986doi = 10.1046/j.1467-789x.2000.00020.xs2cid = 20553857 }}1520
(R)-Desmethylsibutramine444
(S)-Desmethylsibutramine9,200870
author6-link=Bryan Rothvauthors = Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BLtitle = Neurochemical profiles of some novel psychoactive substancesjournal = Eur. J. Pharmacol.volume = 700issue = 1–3pages = 147–51year = 2013pmid = 23261499pmc = 3582025doi = 10.1016/j.ejphar.2012.12.006 }}53,700550
vauthors = Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree THtitle = Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitorjournal = J. Pharmacol. Exp. Ther.volume = 318issue = 2pages = 657–65year = 2006pmid = 16675639doi = 10.1124/jpet.106.103382s2cid = 15063064 }}47531
Didesmethylsibutramine2015
(R)-Didesmethylsibutramine14013
(S)-Didesmethylsibutramine4,30062
Diphenhydramine3,800960
Dosulepin (dothiepin)8.646
Doxepin6829.5
vauthors = Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJtitle = Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinityjournal = Biol. Psychiatryvolume = 55issue = 3pages = 320–2year = 2004pmid = 14744476doi = 10.1016/j.biopsych.2003.07.006s2cid = 29448095 }}3.720
Etoperidone89020,000
Eutylone6901,280
Femoxetine11.0760
Fluoxetine0.81240
Fluvoxamine2.21,300
GBR-12935289277
HydroxybupropionND1.7 (IC50)
Imipramine1.4037
Indatraline3.1012.6
Iprindole1,6201,262
Lofepramine705.4
Maprotiline5,80011.1
Mazindol390.45
3,34926
Methamphetamine100,000ND
D-Methamphetamine100,000660
L-Methamphetamine100,000ND
Methylphenidate10,000788
D-Methylphenidate10,000206
L-Methylphenidate6,70010,000
Mianserin4,00071
Milnacipran*15168
vauthors = Auclair AL, Martel JC, Assié MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortère Rtitle = Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxietyjournal = Neuropharmacologyvolume = 70pages = 338–47year = 2013pmid = 23499664doi = 10.1016/j.neuropharm.2013.02.024doi-access = free }}19.010.5
Mirtazapine100,0004,600
vauthors = Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MHtitle = Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafiniljournal = J. Pharmacol. Exp. Ther.volume = 329issue = 2pages = 738–46year = 2009pmid = 19197004pmc = 2672878doi = 10.1124/jpet.108.146142 }}50,000136,000
Nefazodone200360
vauthors = Gregori-Puigjané E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BKtitle = Identifying mechanism-of-action targets for drugs and probesjournal = Proc. Natl. Acad. Sci. U.S.A.volume = 109issue = 28pages = 11178–83year = 2012pmid = 22711801pmc = 3396511doi = 10.1073/pnas.1204524109bibcode = 2012PNAS..10911178Gdoi-access = free }}2933
Nisoxetine4272.3
Nomifensine1,01015.6
Norfluoxetine1.471,426
Nortriptyline184.37
Oxaprotiline3,9004.9
Paroxetine0.1340
Protriptyline19.61.41
vauthors = Bymaster FP, McNamara RK, Tran PVtitle = New approaches to developing antidepressants by enhancing monoaminergic neurotransmissionjournal = Expert Opin Investig Drugsvolume = 12issue = 4pages = 531–43year = 2003pmid = 12665410doi = 10.1517/13543784.12.4.531s2cid = 20039451 }}1291.1
Sertraline0.29420
Sibutramine298–2,800350–5,451
Trazodone1608,500
Trimipramine1492,450
Vanoxerine73.279.2
Venlafaxine*1451,420
vauthors = Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, Lucki Ititle = Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonistjournal = J. Pharmacol. Exp. Ther.volume = 302issue = 3pages = 1220–7year = 2002pmid = 12183683doi = 10.1124/jpet.102.034280s2cid = 12020750 }}0.2~60
Viloxazine17,300155
vauthors = Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TBtitle = Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorderjournal = J. Med. Chem.volume = 54issue = 9pages = 3206–21year = 2011pmid = 21486038doi = 10.1021/jm101459g }}5.4890 (rat)
Zimelidine1529,400
Values are Ki (nM) or, in some cases, when denoted by an asterisk (*), (nM). The smaller the value, the more strongly the drug binds to or inhibits the transporter.

References

References

  1. (June 2010). "Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat". Neuropsychopharmacology.
  2. (16 July 2008). "Lippincott's Illustrated Reviews: Pharmacology". Lippincott Williams & Wilkins.
  3. (October 2010). "Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats Than in Adult Male Rats". The Journal of Pharmacology and Experimental Therapeutics.
  4. (2008). "Encyclopedia of Molecular Pharmacology". Springer.
  5. (15 April 2011). "Lowinson and Ruiz's Substance Abuse: A Comprehensive Textbook". Lippincott Williams & Wilkins.
  6. (November 2011). "4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse". The Journal of Pharmacology and Experimental Therapeutics.
  7. (July 2022). ["Pharmacological profile of antidepressants and related compounds at human monoamine transporters"](https://www.academia.edu/download/45762636/s0014-2999_2897_2901393-920160518-31441-t07hp6.pdf}}{{dead link). Eur. J. Pharmacol..
  8. (1986). "Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain". Br. J. Pharmacol..
  9. (1989). "Pharmacology of amineptine: synthesis and updating". Clin Neuropharmacol.
  10. (2002). "[Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]". Encephale.
  11. (2003). "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol..
  12. "EMCDDA–Europol Joint Report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP)".
  13. (2000). "An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action". Obes Rev.
  14. (2013). "Neurochemical profiles of some novel psychoactive substances". Eur. J. Pharmacol..
  15. (2006). "Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor". J. Pharmacol. Exp. Ther..
  16. (2004). "Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity". Biol. Psychiatry.
  17. (April 2021). "Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation". ACS Chem Neurosci.
  18. (September 2004). "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors.". Molecular Pharmacology.
  19. (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology.
  20. (2013). "Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety". Neuropharmacology.
  21. (2009). "Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil". J. Pharmacol. Exp. Ther..
  22. (2012). "Identifying mechanism-of-action targets for drugs and probes". Proc. Natl. Acad. Sci. U.S.A..
  23. (2003). "New approaches to developing antidepressants by enhancing monoaminergic neurotransmission". Expert Opin Investig Drugs.
  24. (2002). "Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist". J. Pharmacol. Exp. Ther..
  25. (2011). "Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder". J. Med. Chem..
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