# Monoamine reuptake inhibitor

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 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. 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

Binding profiles of MRIs at human MATs :
| 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* | >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 | 1.1 | 7,841 | 27,410 | SRI | SSRI |
| Clomipramine | 0.28 | 38 | 2,190 | SNRI | TCA |
| Cocaethylene | 3,878 | >10,000 | 555 | SDRI | Stimulant |
| Cocaine | 304 | 779 | 478 | SNDRI | Stimulant |
| Cocaine | 313±17 (IC$_{50}$) | 292±34 (IC$_{50}$) | 211±19 (IC$_{50}$) | 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 | 15 | 20 | 49 | SNDRI | SNRI |
| (R)-Desmethylsibutramine | 44 | 4 | 12 | SNDRI | SNRI |
| (S)-Desmethylsibutramine | 9,200 | 870 | 180 | SNDRI | SNRI |
| Desoxypipradrol | 53,700 | 550 | 50 | NDRI | Stimulant |
| Desvenlafaxine* | 47 | 531 | ND | SNRI | SNRI |
| Didesmethylsibutramine | 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* | 3.7 | 20 | 439 | SNRI | SNRI |
| Etoperidone | 890 | 20,000 | 52,000 | SRI | SARI |
| Eutylone | 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 | 289 | 277 | 4.90 | DRI | Stimulant |
| Hydroxybupropion | ND | 1.7 (IC$_{50}$) | >10 (IC$_{50}$) | NDRI | Stimulant |
| Imipramine | 1.40 | 37 | 8,500 | SNRI | TCA |
| Indatraline | 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 | 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* | 151 | 68 | >100,000 | SNRI | SNRI |
| Levomilnacipran* | 19.0 | 10.5 | >100,000 | SNRI | SNRI |
| Mirtazapine | >100,000 | 4,600 | >100,000 | N/A (IA) | TeCA |
| Modafinil* | >50,000 | 136,000 | 4,043 | DRI | Stimulant |
| Nefazodone | 200 | 360 | 360 | SNDRI | SARI |
| Nefopam | 29 | 33 | 531 | SNDRI | Analgesic |
| Nisoxetine | 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 | 129 | 1.1 | >10,000 | NRI | Stimulant |
| Sertraline | 0.29 | 420 | 25 | SRI | SSRI |
| Sibutramine | 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 | 73.2 | 79.2 | 4.3 | DRI | Stimulant |
| Venlafaxine* | 145 | 1,420 | 3,070 | SNRI | SNRI |
| Vilazodone* | 0.2 | ~60 | ND | SRI | SMS |
| Viloxazine | 17,300 | 155 | >100,000 | NRI | Stimulant |
| Vortioxetine* | 5.4 | 890 (rat) | 140 (rat) | SRI | SMS |
| Zimelidine | 152 | 9,400 | 11,700 | SRI | SSRI |
| Values are K$_i$ (nM) or, in some cases, when denoted by an asterisk (*), IC$_{50}$Tooltip half-maximal inhibitory concentration (nM). The smaller the value, the more strongly the drug binds to or inhibits the transporter. ||||||