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
editThe 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 ADHD 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
editThere 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
editCompound | SERT | NET | DAT | Type | Class | |
---|---|---|---|---|---|---|
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 | |
MDPV[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 (*), IC50 (nM). The smaller the value, the more strongly the drug binds to or inhibits the transporter. |
See also
editReferences
edit- ^ 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.
- ^ 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.
- ^ 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.
- ^ Stefan Offermanns; Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. p. 1039. ISBN 978-3-540-38916-3. Retrieved 12 May 2012.
- ^ Pedro Ruiz; Eric C. Strain (15 April 2011). Lowinson and Ruiz's Substance Abuse: A Comprehensive Textbook. Lippincott Williams & Wilkins. p. 55. ISBN 978-1-60547-277-5. Retrieved 12 May 2012.
- ^ Hadlock GC, Webb KM, McFadden LM, et al. (November 2011). "4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse". The Journal of Pharmacology and Experimental Therapeutics. 339 (2): 530–6. doi:10.1124/jpet.111.184119. PMC 3200001. PMID 21810934.
- ^ Tatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters" (PDF). Eur. J. Pharmacol. 340 (2–3): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID 9537821.[dead link]
- ^ Ceci A, Garattini S, Gobbi M, Mennini T (1986). "Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain". Br. J. Pharmacol. 88 (1): 269–75. doi:10.1111/j.1476-5381.1986.tb09495.x. PMC 1917102. PMID 3708219.
- ^ Garattini S, Mennini T (1989). "Pharmacology of amineptine: synthesis and updating". Clin Neuropharmacol. 12 Suppl 2: S13–8. doi:10.1097/00002826-198912002-00003. PMID 2698268. S2CID 10947713.
- ^ Owens JM, Knight DL, Nemeroff CB (2002). "[Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]". Encephale (in French). 28 (4): 350–5. PMID 12232544.
- ^ a b c d e f Rothman RB, Baumann MH (2003). "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
- ^ "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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Auclair AL, Martel JC, Assié MB, Bardin L, Heusler P, Cussac D, Marien M, Newman-Tancredi A, O'Connor JA, Depoortère R (2013). "Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety". Neuropharmacology. 70: 338–47. doi:10.1016/j.neuropharm.2013.02.024. PMID 23499664.
- ^ 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.
- ^ 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.
- ^ Bymaster FP, McNamara RK, Tran PV (2003). "New approaches to developing antidepressants by enhancing monoaminergic neurotransmission". Expert Opin Investig Drugs. 12 (4): 531–43. doi:10.1517/13543784.12.4.531. PMID 12665410. S2CID 20039451.
- ^ 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.
- ^ 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.
External links
edit- Media related to Monoamine reuptake inhibitors at Wikimedia Commons