Monoamine reuptake inhibitor explained
A monoamine reuptake inhibitor (MRI)[1] 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).[2] 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.[3] [4] Additionally, psychostimulants acting as MRIs that affect dopamine such as cocaine and methylphenidate are often abused as recreational drugs.[5] 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.[6]
Types of MRIs
There are a variety of different kinds of MRIs, of which include the following:
- Specific for one monoamine transporter
- Non-specific, binding to two or more monoamine transporters
Binding profiles
Binding profiles of at human [7] | Compound | | | | Type | Class |
|---|
| | | 207 | DRI | Stimulant |
| Amineptine
| >100,000 (rat) | 10,000 (rat) | 1,000–1,400 (rat) | DRI | Stimulant |
| 4.30 | 35 | 3,250 | SNRI | TCA |
| 58 | 16.0 | 4,310 | SNRI | |
| >100,000 | | | | Stimulant |
| >100,000 | 530 | 2,900 | NDRA | Stimulant |
| >100,000 | | | | Stimulant |
| 77 | 5 | 1,451 | NRI | Stimulant |
| 9,100 | 52,000 | 520 | NDRI | Stimulant |
| 1,360 | 5,100 | 3,940 | N/A | TCA |
| 15.2 | 1,440 | 1,060 | SRI | Antihistamine |
| 1.16 | 4,070 | 28,100 | SRI | |
| Escitalopram[10] | 1.1 | 7,841 | 27,410 | SRI | SSRI |
| 0.28 | 38 | 2,190 | SNRI | TCA |
| Cocaethylene[11] | 3,878 | >10,000 | 555 | SDRI | Stimulant |
| 304 | 779 | 478 | SNDRI | Stimulant |
| Cocaine[12] | 313±17 (IC50) | 292±34 (IC50) | 211±19 (IC50) | SNDRI | Stimulant |
| 17.6 | 0.83 | 3,190 | SNRI | TCA |
| 3.6 | 1,820 | 18,300 | SRI | SSRI |
| 3.0 | 390 | 129 | SRI | SSRI |
| Desmethylsibutramine[13] | 15 | 20 | 49 | SNDRI | SNRI |
| 44 | 4 | 12 | SNDRI | SNRI |
| 9,200 | 870 | 180 | SNDRI | SNRI |
| Desoxypipradrol[14] | 53,700 | 550 | 50 | NDRI | Stimulant |
| Desvenlafaxine
| 47 | 531 | | SNRI | SNRI |
| 20 | 15 | 45 | SNDRI | SNRI |
| 140 | 13 | 8.9 | SNDRI | SNRI |
| 4,300 | 62 | 12 | SNDRI | SNRI |
| 3,800 | 960 | 2,200 | N/A | Antihistamine |
| 8.6 | 46 | 5,310 | SNRI | TCA |
| 68 | 29.5 | 12,100 | SNRI | TCA |
| Duloxetine
| 3.7 | 20 | 439 | SNRI | SNRI |
| 890 | 20,000 | 52,000 | SRI | |
| 11.0 | 760 | 2,050 | SRI | SSRI |
| 0.81 | 240 | 3,600 | SRI | SSRI |
| 2.2 | 1,300 | 9,200 | SRI | SSRI |
| 289 | 277 | 4.90 | DRI | Stimulant |
| Hydroxybupropion[17] | | 1.7 (IC50) | >10 (IC50) | NDRI | Stimulant |
| 1.40 | 37 | 8,500 | SNRI | TCA |
| 3.10 | 12.6 | 1.90 | SNDRI | Stimulant |
| 1,620 | 1,262 | 6,530 | N/A | TCA |
| 70 | 5.4 | 18,000 | SNRI | TCA |
| 5,800 | 11.1 | 1,000 | NRI | TeCA |
| 39 | 0.45 | 8.1 | NDRI | Stimulant |
| [18] | 3,349 | 26 | 4.1 | NDRI | Stimulant |
| >100,000 | | | NDRA | Stimulant |
| >100,000 | 660 | 2,800 | NDRA | Stimulant |
| >100,000 | | | NRA | Stimulant |
| >10,000 | 788 | 121 | NDRI | Stimulant |
| >10,000 | 206 | 161 | NDRI | Stimulant |
| >6,700 | >10,000 | 2,250 | NDRI | Stimulant |
| 4,000 | 71 | 9,400 | NRI | TeCA |
| Milnacipran | 151 | 68 | >100,000 | SNRI | SNRI |
| Levomilnacipran*[19] | 19.0 | 10.5 | >100,000 | SNRI | SNRI |
| >100,000 | 4,600 | >100,000 | N/A | TeCA |
| Modafinil
| >50,000 | 136,000 | 4,043 | DRI | Stimulant |
| 200 | 360 | 360 | SNDRI | SARI |
| Nefopam[21] | 29 | 33 | 531 | SNDRI | Analgesic |
| 427 | 2.3 | 1,235 | NRI | Stimulant |
| 1,010 | 15.6 | 56 | NDRI | Stimulant |
| 1.47 | 1,426 | 420 | SRI | SSRI |
| 18 | 4.37 | 1,140 | SNRI | TCA |
| 3,900 | 4.9 | 4,340 | NRI | TeCA |
| 0.13 | 40 | 490 | SRI | SSRI |
| 19.6 | 1.41 | 2,100 | SNRI | TCA |
| Reboxetine[22] | 129 | 1.1 | >10,000 | NRI | Stimulant |
| 0.29 | 420 | 25 | SRI | SSRI |
| 298–2,800 | 350–5,451 | 943–1,200 | SNDRI | SNRI |
| 160 | 8,500 | 7,400 | SRI | SARI |
| 149 | 2,450 | 3,780 | SRI | TCA |
| 73.2 | 79.2 | 4.3 | DRI | Stimulant |
| Venlafaxine | 145 | 1,420 | 3,070 | SNRI | SNRI |
| Vilazodone
| 0.2 | ~60 | | SRI | |
| 17,300 | 155 | >100,000 | NRI | Stimulant |
| Vortioxetine
| 5.4 | 890 (rat) | 140 (rat) | SRI | SMS |
| 152 | 9,400 | 11,700 | SRI | SSRI |
Values are Ki (nM) or, in some cases (*), (nM). The smaller the value, the more strongly the
drug binds to or inhibits the transporter. | |
See also
Notes and References
- Axel AM, Mikkelsen JD, Hansen HH . 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 . 35 . 7 . 1464–76 . June 2010 . 20200509 . 3055463 . 10.1038/npp.2010.16 .
- Book: Richard Finkel . Michelle Alexia Clark . Pamela C. Champe . Luigi X. Cubeddu . Lippincott's Illustrated Reviews: Pharmacology . 12 May 2012 . 16 July 2008 . Lippincott Williams & Wilkins . 978-0-7817-7155-9 . 141.
- Walker. Q. David. Morris. Sarah E.. Arrant. Andrew E.. Nagel. Jacqueline M.. Parylak. Sarah. Zhou. Guiying. Caster. Joseph M.. Kuhn. Cynthia M.. 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. 335. 1. 124–132. 10.1124/jpet.110.167320. 0022-3565. 2957786. 20605908.
- Book: Stefan Offermanns . Walter Rosenthal . Encyclopedia of Molecular Pharmacology . 12 May 2012 . 2008 . Springer . 978-3-540-38916-3 . 1039.
- Book: Pedro Ruiz . Eric C. Strain . Lowinson and Ruiz's Substance Abuse: A Comprehensive Textbook . 12 May 2012 . 15 April 2011 . Lippincott Williams & Wilkins . 978-1-60547-277-5 . 55.
- Hadlock GC, Webb KM, McFadden LM, etal . 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse . The Journal of Pharmacology and Experimental Therapeutics . 339 . 2 . 530–6 . November 2011 . 21810934 . 10.1124/jpet.111.184119 . 3200001.
- Tatsumi M, Groshan K, Blakely RD, Richelson E . Pharmacological profile of antidepressants and related compounds at human monoamine transporters . Eur. J. Pharmacol. . 340 . 2–3 . 249–58 . 1997 . 9537821 . 10.1016/s0014-2999(97)01393-9.
- Ceci A, Garattini S, Gobbi M, Mennini T . Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain . Br. J. Pharmacol. . 88 . 1 . 269–75 . 1986 . 3708219 . 1917102 . 10.1111/j.1476-5381.1986.tb09495.x.
- Garattini S, Mennini T . Pharmacology of amineptine: synthesis and updating . Clin Neuropharmacol . 12 Suppl 2 . S13–8 . 1989 . 2698268 . 10.1097/00002826-198912002-00003. 10947713 .
- Owens JM, Knight DL, Nemeroff CB . [Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine] . fr . Encephale . 28 . 4 . 350–5 . 2002 . 12232544 .
- Rothman RB, Baumann MH . Monoamine transporters and psychostimulant drugs . Eur. J. Pharmacol. . 479 . 1–3 . 23–40 . 2003 . 14612135 . 10.1016/j.ejphar.2003.08.054.
- Web site: EMCDDA–Europol Joint Report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP) . www.euda.europa.eu . 2024-07-16.
- Nisoli E, Carruba MO . An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action . Obes Rev . 1 . 2 . 127–39 . 2000 . 12119986 . 10.1046/j.1467-789x.2000.00020.x. 20553857 .
- Bryan Roth . Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL . Neurochemical profiles of some novel psychoactive substances . Eur. J. Pharmacol. . 700 . 1–3 . 147–51 . 2013 . 23261499 . 3582025 . 10.1016/j.ejphar.2012.12.006 .
- Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH . Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor . J. Pharmacol. Exp. Ther. . 318 . 2 . 657–65 . 2006 . 16675639 . 10.1124/jpet.106.103382 . 15063064 .
- Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ . Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity . Biol. Psychiatry . 55 . 3 . 320–2 . 2004 . 14744476 . 10.1016/j.biopsych.2003.07.006 . 29448095 .
- Damaj . MI . Carroll . FI . Eaton . JB . Navarro . HA . Blough . BE . Mirza . S . Lukas . RJ . Martin . BR . Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. . Molecular Pharmacology . September 2004 . 66 . 3 . 675–82 . 10.1124/mol.104.001313 . 15322260 . 1577336 .
- Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW . Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products . Neuropsychopharmacology . 38 . 4 . 552–62 . 2013 . 23072836 . 3572453 . 10.1038/npp.2012.204 .
- Auclair AL, Martel JC, Assié MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortère R . Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety . Neuropharmacology . 70 . 338–47 . 2013 . 23499664 . 10.1016/j.neuropharm.2013.02.024 . free .
- Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH . Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil . J. Pharmacol. Exp. Ther. . 329 . 2 . 738–46 . 2009 . 19197004 . 2672878 . 10.1124/jpet.108.146142 .
- Gregori-Puigjané E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BK . Identifying mechanism-of-action targets for drugs and probes . Proc. Natl. Acad. Sci. U.S.A. . 109 . 28 . 11178–83 . 2012 . 22711801 . 3396511 . 10.1073/pnas.1204524109 . 2012PNAS..10911178G . free .
- Bymaster FP, McNamara RK, Tran PV . New approaches to developing antidepressants by enhancing monoaminergic neurotransmission . Expert Opin Investig Drugs . 12 . 4 . 531–43 . 2003 . 12665410 . 10.1517/13543784.12.4.531 . 20039451 .
- Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, Lucki I . 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. . 302 . 3 . 1220–7 . 2002 . 12183683 . 10.1124/jpet.102.034280 . 12020750 .
- Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB . 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. . 54 . 9 . 3206–21 . 2011 . 21486038 . 10.1021/jm101459g .
