Chemistry:Monoamine reuptake inhibitor
From HandWiki
Short description: Drug class
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 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
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
| Compound | SERT | NET | DAT | 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 | |
| Desvenlafaxine*[14] | 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*[15] | 3.7 | 20 | 439 | SNRI | SNRI | |
| Etoperidone | 890 | 20,000 | 52,000 | SRI | SARI | |
| Eutylone[16] | 690 | 1,280 | 120 | SNDRI | Stimulant | |
| 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 | |
| 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*[15] | 151 | 68 | >100,000 | SNRI | SNRI | |
| Levomilnacipran*[18] | 19.0 | 10.5 | >100,000 | SNRI | SNRI | |
| Mirtazapine | >100,000 | 4,600 | >100,000 | N/A (IA) | TeCA | |
| Modafinil*[19] | >50,000 | 136,000 | 4,043 | DRI | Stimulant | |
| Nefazodone | 200 | 360 | 360 | SNDRI | SARI | |
| Nefopam[20] | 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[21] | 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*[15] | 145 | 1,420 | 3,070 | SNRI | SNRI | |
| Vilazodone*[22] | 0.2 | ~60 | ND | SRI | SMS | |
| Viloxazine | 17,300 | 155 | >100,000 | NRI | Stimulant | |
| Vortioxetine*[23] | 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 (*), IC50 (nM). The smaller the value, the more strongly the drug binds to or inhibits the transporter. | ||||||
See also
References
- ↑ "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. doi:10.1038/npp.2010.16. 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. https://books.google.com/books?id=Q4hG2gRhy7oC&pg=PA141. 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. PMID 20605908.
- ↑ Stefan Offermanns; Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. p. 1039. ISBN 978-3-540-38916-3. https://books.google.com/books?id=fGe6NDIGQpsC&pg=PA1039. 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. https://books.google.com/books?id=w4ZUJAdleTsC&pg=PA55. Retrieved 12 May 2012.
- ↑ "4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse". The Journal of Pharmacology and Experimental Therapeutics 339 (2): 530–6. November 2011. doi:10.1124/jpet.111.184119. PMID 21810934.
- ↑ "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2–3): 249–58. 1997. doi:10.1016/s0014-2999(97)01393-9. PMID 9537821. https://www.academia.edu/download/45762636/s0014-2999_2897_2901393-920160518-31441-t07hp6.pdf.
- ↑ "Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain". Br. J. Pharmacol. 88 (1): 269–75. 1986. doi:10.1111/j.1476-5381.1986.tb09495.x. PMID 3708219.
- ↑ "Pharmacology of amineptine: synthesis and updating". Clin Neuropharmacol 12 Suppl 2: S13–8. 1989. doi:10.1097/00002826-198912002-00003. PMID 2698268.
- ↑ "[Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]" (in fr). Encephale 28 (4): 350–5. 2002. PMID 12232544.
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol. 479 (1–3): 23–40. 2003. 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)". https://www.euda.europa.eu/publications/joint-reports/alpha-pvp_en.
- ↑ 13.0 13.1 13.2 "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. doi:10.1046/j.1467-789x.2000.00020.x. PMID 12119986.
- ↑ "Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor". J. Pharmacol. Exp. Ther. 318 (2): 657–65. 2006. doi:10.1124/jpet.106.103382. PMID 16675639.
- ↑ 15.0 15.1 15.2 "Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity". Biol. Psychiatry 55 (3): 320–2. 2004. doi:10.1016/j.biopsych.2003.07.006. PMID 14744476.
- ↑ "Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation". ACS Chem Neurosci 12 (7): 1172. April 2021. doi:10.1021/acschemneuro.0c00797. PMID 33689284. PMC 9423000. https://pubs.acs.org/doi/10.1021/acschemneuro.0c00797.
- ↑ 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.
- ↑ "Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety". Neuropharmacology 70: 338–47. 2013. doi:10.1016/j.neuropharm.2013.02.024. PMID 23499664.
- ↑ "Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil". J. Pharmacol. Exp. Ther. 329 (2): 738–46. 2009. doi:10.1124/jpet.108.146142. PMID 19197004.
- ↑ "Identifying mechanism-of-action targets for drugs and probes". Proc. Natl. Acad. Sci. U.S.A. 109 (28): 11178–83. 2012. doi:10.1073/pnas.1204524109. PMID 22711801. Bibcode: 2012PNAS..10911178G.
- ↑ "New approaches to developing antidepressants by enhancing monoaminergic neurotransmission". Expert Opin Investig Drugs 12 (4): 531–43. 2003. doi:10.1517/13543784.12.4.531. PMID 12665410.
- ↑ "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. doi:10.1124/jpet.102.034280. PMID 12183683.
- ↑ "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. doi:10.1021/jm101459g. PMID 21486038.
External links
 |  |
