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Monoamine reuptake inhibitor

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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

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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 ADHDTooltip attention-deficit hyperactivity disorder 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

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

Binding profiles

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See also: Monoamine releasing agent § Activity profiles
Binding profiles of MRIs at human MATs[7]
Compound SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter Type Class
3-Methylmethcathinone 4500 80 270 NDRI Stimulant
Amfonelic acid ND ND 207 DRI Stimulant
Amineptine*[8][9] >100,000 (rat) 10,000 (rat) 1,000–1,400 (rat) DRI Stimulant
Amitriptyline 4.30 35 3,250 SNRI TCA
Amoxapine 58 16.0 4,310 SNRI TeCA
Amphetamine >100,000 ND ND NDRA Stimulant
  D-Amphetamine >100,000 530 2,900 NDRA Stimulant
  L-Amphetamine >100,000 ND ND NRA Stimulant
Atomoxetine 77 5 1,451 NRI Stimulant
Bupropion 9,100 52,000 520 NDRI Stimulant
Butriptyline 1,360 5,100 3,940 N/A (IA) TCA
Chlorphenamine 15.2 1,440 1,060 SRI Antihistamine
Citalopram 1.16 4,070 28,100 SRI SSRI
  Escitalopram[10] 1.1 7,841 27,410 SRI SSRI
Clomipramine 0.28 38 2,190 SNRI TCA
Cocaethylene[11] 3,878 >10,000 555 SDRI Stimulant
Cocaine[11] 304 779 478 SNDRI Stimulant
Cocaine[12] 313±17 (IC50) 292±34 (IC50) 211±19 (IC50) SNDRI Stimulant
Desipramine 17.6 0.83 3,190 SNRI TCA
Desmethylcitalopram 3.6 1,820 18,300 SRI SSRI
Desmethylsertraline 3.0 390 129 SRI SSRI
Desmethylsibutramine[13] 15 20 49 SNDRI SNRI
  (R)-Desmethylsibutramine 44 4 12 SNDRI SNRI
  (S)-Desmethylsibutramine 9,200 870 180 SNDRI SNRI
Desoxypipradrol[14] 53,700 550 50 NDRI Stimulant
Desvenlafaxine*[15] 47 531 ND SNRI SNRI
Didesmethylsibutramine[13] 20 15 45 SNDRI SNRI
  (R)-Didesmethylsibutramine 140 13 8.9 SNDRI SNRI
  (S)-Didesmethylsibutramine 4,300 62 12 SNDRI SNRI
Diphenhydramine 3,800 960 2,200 N/A (IA) Antihistamine
Dosulepin (dothiepin) 8.6 46 5,310 SNRI TCA
Doxepin 68 29.5 12,100 SNRI TCA
Duloxetine*[16] 3.7 20 439 SNRI SNRI
Etoperidone 890 20,000 52,000 SRI SARI
Femoxetine 11.0 760 2,050 SRI SSRI
Fluoxetine 0.81 240 3,600 SRI SSRI
Fluvoxamine 2.2 1,300 9,200 SRI SSRI
GBR-12935[11] 289 277 4.90 DRI Stimulant
Hydroxybupropion[17] ND 1.7 (IC50) >10 (IC50) NDRI Stimulant
Imipramine 1.40 37 8,500 SNRI TCA
Indatraline[11] 3.10 12.6 1.90 SNDRI Stimulant
Iprindole 1,620 1,262 6,530 N/A (IA) TCA
Lofepramine 70 5.4 18,000 SNRI TCA
Maprotiline 5,800 11.1 1,000 NRI TeCA
Mazindol 39 0.45 8.1 NDRI Stimulant
MDPVTooltip Methylenedioxypyrovalerone[18] 3,349 26 4.1 NDRI Stimulant
Methamphetamine >100,000 ND ND NDRA Stimulant
  D-Methamphetamine >100,000 660 2,800 NDRA Stimulant
  L-Methamphetamine >100,000 ND ND NRA Stimulant
Methylphenidate >10,000 788 121 NDRI Stimulant
  D-Methylphenidate >10,000 206 161 NDRI Stimulant
  L-Methylphenidate >6,700 >10,000 2,250 NDRI Stimulant
Mianserin 4,000 71 9,400 NRI TeCA
Milnacipran*[16] 151 68 >100,000 SNRI SNRI
  Levomilnacipran*[19] 19.0 10.5 >100,000 SNRI SNRI
Mirtazapine >100,000 4,600 >100,000 N/A (IA) TeCA
Modafinil*[20] >50,000 136,000 4,043 DRI Stimulant
Nefazodone 200 360 360 SNDRI SARI
Nefopam[21] 29 33 531 SNDRI Analgesic
Nisoxetine[11] 427 2.3 1,235 NRI Stimulant
Nomifensine 1,010 15.6 56 NDRI Stimulant
Norfluoxetine 1.47 1,426 420 SRI SSRI
Nortriptyline 18 4.37 1,140 SNRI TCA
Oxaprotiline 3,900 4.9 4,340 NRI TeCA
Paroxetine 0.13 40 490 SRI SSRI
Protriptyline 19.6 1.41 2,100 SNRI TCA
Reboxetine[22] 129 1.1 >10,000 NRI Stimulant
Sertraline 0.29 420 25 SRI SSRI
Sibutramine[13] 298–2,800 350–5,451 943–1,200 SNDRI SNRI
Trazodone 160 8,500 7,400 SRI SARI
Trimipramine 149 2,450 3,780 SRI TCA
Vanoxerine[11] 73.2 79.2 4.3 DRI Stimulant
Venlafaxine*[16] 145 1,420 3,070 SNRI SNRI
Vilazodone*[23] 0.2 ~60 ND SRI SMS
Viloxazine 17,300 155 >100,000 NRI Stimulant
Vortioxetine*[24] 5.4 890 (rat) 140 (rat) SRI SMS
Zimelidine 152 9,400 11,700 SRI SSRI
Values are Ki (nM) or, in some cases, when denoted by an asterisk (*), IC50Tooltip half-maximal inhibitory concentration (nM). The smaller the value, the more strongly the drug binds to or inhibits the transporter.

See also

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References

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  1. ^ Axel AM, Mikkelsen JD, Hansen HH (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. 35 (7): 1464–76. doi:10.1038/npp.2010.16. PMC 3055463. PMID 20200509.
  2. ^ Richard Finkel; Michelle Alexia Clark; Pamela C. Champe; Luigi X. Cubeddu (16 July 2008). Lippincott's Illustrated Reviews: Pharmacology. Lippincott Williams & Wilkins. p. 141. ISBN 978-0-7817-7155-9. Retrieved 12 May 2012.
  3. ^ 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. doi:10.1124/jpet.110.167320. ISSN 0022-3565. PMC 2957786. PMID 20605908.
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  12. ^ "EMCDDA–Europol Joint Report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP)". www.euda.europa.eu. Retrieved 2024-07-16.
  13. ^ a b c Nisoli E, Carruba MO (2000). "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. doi:10.1046/j.1467-789x.2000.00020.x. PMID 12119986. S2CID 20553857.
  14. ^ Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL (2013). "Neurochemical profiles of some novel psychoactive substances". Eur. J. Pharmacol. 700 (1–3): 147–51. doi:10.1016/j.ejphar.2012.12.006. PMC 3582025. PMID 23261499.
  15. ^ Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, Andree TH (2006). "Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor". J. Pharmacol. Exp. Ther. 318 (2): 657–65. doi:10.1124/jpet.106.103382. PMID 16675639. S2CID 15063064.
  16. ^ a b c Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ (2004). "Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity". Biol. Psychiatry. 55 (3): 320–2. doi:10.1016/j.biopsych.2003.07.006. PMID 14744476. S2CID 29448095.
  17. ^ Damaj, MI; Carroll, FI; Eaton, JB; Navarro, HA; Blough, BE; Mirza, S; Lukas, RJ; Martin, BR (September 2004). "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors". Molecular Pharmacology. 66 (3): 675–82. doi:10.1124/mol.104.001313. PMID 15322260. S2CID 1577336.
  18. ^ 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 (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–62. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
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  20. ^ Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (2009). "Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil". J. Pharmacol. Exp. Ther. 329 (2): 738–46. doi:10.1124/jpet.108.146142. PMC 2672878. PMID 19197004.
  21. ^ Gregori-Puigjané E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BK (2012). "Identifying mechanism-of-action targets for drugs and probes". Proc. Natl. Acad. Sci. U.S.A. 109 (28): 11178–83. Bibcode:2012PNAS..10911178G. doi:10.1073/pnas.1204524109. PMC 3396511. PMID 22711801.
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  23. ^ Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, Lucki I (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. 302 (3): 1220–7. doi:10.1124/jpet.102.034280. PMID 12183683. S2CID 12020750.
  24. ^ Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB (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. 54 (9): 3206–21. doi:10.1021/jm101459g. PMID 21486038.
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