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Wikipedia / Serotonin–norepinephrine–dopamine reuptake inhibitor

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI or TUI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine, resulting in increased signaling in associated neurological systems.

SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention deficit hyperactivity disorder (ADHD), and chronic pain. The goal of such development was improved efficacy or tolerability over existing selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and dopamine–norepinephrine reuptake inhibitors (NDRIs). However, increased side effects and abuse potential are concerns when using these agents, relative to their more selective counterparts.

SNDRIs include the naturally occurring drug cocaine, a widely used recreational and often illegal drug for the euphoric effects it produces. Additionally, MDMA, another common drug of abuse, is also an SNDRI, however its reuptake inhibition is comparatively weak compared to its properties as a serotonin–dopamine–norepinephrine releasing agent.

Indications

SNDRIs have been studied for a number of indications, but primarily for that of depression, and ADHD.

Preclinical and clinical research indicates that drugs inhibiting the reuptake of all three of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants.

Applications other than depression

Cocaine

Cocaine is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. Cocaine users may experience symptoms of extreme fatigue, decreased mood, and a "crash" following the original euphoria of the drug; subsequent to the crash, users begin to crave for more. In addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anesthetic activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.

Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure. There has been speculation over whether the new SNDRIs will have an abuse potential like cocaine does. However, for pharmacotherapeutics, treatment of cocaine addiction is advantageous if a substitute medication is at least weakly reinforcing because it can serve to retain addicts in treatment programs.

Legality

Cocaine is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some "abuse potential" it is recognized as useful for surgery considering it is a local anesthetic that can be applied to areas such as the nose, mouth, or throat for numbing purposes.

Brasofensine, a dopamine inhibitor developed to treat Parkinson's disease, was made "class A" in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making brasofensine uses cocaine as the starting material.

Naphyrone, a drug that inhibits monoamine transporters, first appeared in 2006 as one of quite a large number of analogs of pyrovalerone designed by the well-known medicinal chemist P. Meltzer et al. When the designer drugs mephedrone and methylone became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine releasers and not act through the reuptake inhibitor mechanism of activity. A short time later, mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name NRG-1. NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths.

Self-Administration of Drugs

According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic. This finding has been found for amphetamine and some of its variously substituted analogs including PAL-287 etc. RTI-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter.

Further evidence that 5-HT (serotonin) dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only. However, not all SNDRIs are reliably self-administered by animals. Examples include:

  • PRC200-SS was not reliably self-administered.

  • RTI-112 was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT.

  • Tesofensine was also not reliably self-administered by human stimulant addicts.

  • The nocaine analog JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.

Failure of SNDRIs for depression

SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trials. In addition, the augmentation of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo in phase III clinical trials of individuals with treatment-resistant depression, and clinical development was subsequently discontinued. These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy. As such, skepticism has been cast on the promise of the remaining SNDRIs that are still being trialed, such as ansofaxine (currently in phase II trials), in the treatment of depression. Despite being a weak SNDRI, nefazodone has been successful in treating major depressive disorder.

Known SNDRIS

Approved pharmaceuticals

  • Centanafadine (Simtriyo) — psychostimulant; Received FDA approval in 2026 for the treatment of ADHD in adult and pediatric patients aged 6 and older.

  • Mazindol (Mazanor, Sanorex) — anorectic; ki is 50 nM for SERT, 18 nM for NET, 45 nM for DAT

  • Nefazodone (Serzone, Nefadar, Dutonin) — antidepressant; non-selective; ki is 200 nM at SERT, 360 nM at NET, 360 nM at DAT

  • Nefopam — analgesic, Ki SER/NE/DA = 29/33/531 nM)

  • Toludesvenlafaxine (Ansofaxine, LY03005/LPM570065). Completed Phase 2 & 3 trials. FDA accepted NDA application. Approved in China.

Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with ki values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).https://web.archive.org/web/20090710173718/http://www.fda.gov/downloads/Drugs/DrugSafety/PublicHealthAdvisories/UCM130745.pdf

Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with ki values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.

Coincidental

Undergoing clinical trials

SEP-432 was in stage 1 clinical trials but not yet in stage 2 or stage 3.

  • IC50 values in patent for compound 225: hSERT=7nM, hNET= 23nM, hDAT=167nM. Although in the earlier patent (277 on scheme 36) IC50 values (nM) of hSERT=34, NET=13 & DAT=41.

  • SEP-432 has a chemistry that is related to sibutramine and bromadol & Levocabastine & 3',4'-dichloromeperidine.

Failed clinical trials

Designer drugsDesigner drugs

Research compounds (no record of having been taken by humans)

Lilly group: LR-5182 (maybe only NDRI) (1978) CID:9903806:

NeuroSearch group: NS9775, NS18283. & 4-Benzhydryl-1,2,3,6-tetrahydropyridine [1186529-81-6].

Liming Shao (Sepracor/Sunovion). 3',4'-Dichlorotramadol, CID:53321058 (S/N/D = 19/04/01 nM).

Pfizer group CP-607366 & CP-939689.

Venlafaxine analogues, LPM580098 & LPM580153. And TP1 later reassigned name to PA01.

Albany Molecular Research group (Bruce Molino) AMR-2 (ki is DAT 3.1 nM, SERT 8.3 nM, NET 3.0 nM):

Herbals

  • cocaine — natural alkaloid and drug of abuse extracted from plants of the genus Erythroxylum

  • Ginkgo biloba extract (EGb761) — "The norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro"

St John's Wort — a natural product and over-the-counter herbal antidepressant which contains:

See also

References