# Serotonin–dopamine releasing agent

A serotonin–dopamine releasing agent (SDRA) is a type of drug which induces the release of serotonin and dopamine in the body and/or brain.
SDRAs are rare, owing to the fact that it has proven extremely difficult to dissociate dopamine and norepinephrine release. However, in 2014, the first selective SDRAs, a series of substituted tryptamines, albeit also acting as serotonin receptor agonists, were described.
A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI), for instance UWA-101 (α-cyclopropyl-MDMA).

## Examples of SDRAs

A number of tryptamine derivatives, specifically α-alkyltryptamines, have been found to act as SDRAs. One such agent is 5-chloro-αMT (PAL-542), which has been reported as having about 64-fold selectivity for dopamine release over norepinephrine release and about 3-fold selectivity for serotonin release over dopamine release, making it a highly selective and well-balanced SDRA. Another agent is 5-fluoro-αET (PAL-545), which has about 35-fold selectivity for dopamine release over norepinephrine release and about 4-fold selectivity for serotonin release over dopamine release. Though selective for inducing the release of serotonin and dopamine over norepinephrine, these agents are not selective monoamine releasers; they have all also been found to be potent agonists of the 5-HT$_{2A}$ receptor, and are likely to act as agonists of other serotonin receptors as well. In any case, they are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine.
Another tryptamine SDRA is the β-ketotryptamine BK-NM-AMT (α,N-dimethyl-β-ketotryptamine). It is the N-methyl and β-keto analogue of αMT. The drug is a cathinone-like tryptamine and can be thought of as the tryptamine analogue of methcathinone. Its EC$_{50}$Tooltip half-maximal effective concentration values for monoamine release are 41.3 nM for serotonin and 92.8 nM for dopamine, whereas it only induced 55% release of norepinephrine at a concentration of 10 μM. BK-NM-AMT has been described in a patent filed by Matthew Baggott, assigned to Tactogen, and published in October 2024. 5-Halogenated derivatives of this drug, including BK-5F-NM-AMT, BK-5Cl-NM-AMT, and BK-5Br-NM-AMT, have also been described and patented. Like BK-NM-AMT, they induce serotonin and dopamine release. In contrast to many other tryptamines, these compounds are inactive as agonists of serotonin receptors including the 5-HT$_1$, 5-HT$_2$, and 5-HT$_3$ receptors. In addition, unlike other α-alkyltryptamines like αMT, they are inactive as monoamine oxidase inhibitors (MAOIs).
3-Methoxymethcathinone (3-MeOMC) is a rare possible example of a phenethylamine (or rather cathinone) SDRA. Its EC$_{50}$Tooltip half-maximal effective concentration values for monoamine release are 129 nM for dopamine and 306 nM for serotonin, whereas it only induced 68% release of norepinephrine at 10 μM. However, in another publication, its EC$_{50}$ for induction of norepinephrine release was reported and was 111 nM.
N,N-Dimethyl-4-methylthioamphetamine (N,N-dimethyl-4-MTA; 4-MTDMA, DMMTA) has been described as a releasing agent of serotonin and dopamine that lacks induction of aortic contraction in vitro and hence may lack concomitant norepinephrine release. However, EC$_{50}$ values for monoamine release were not reported. 4-MTDMA is actually a partial releaser of serotonin rather than a full releaser, with a maximal efficacy for induction of serotonin release of either 25% or 50% relative to MDMA or para-chloroamphetamine (PCA) (which are 100% or full releasers). Although 4-MTDMA might not induce norepinephrine release, it is a monoamine oxidase A (MAO-A) inhibitor, with an IC$_{50}$Tooltip half-maximal inhibitory concentration of 2,100 nM.

### Activity profiles

Activity profiles of SDRAs and related compounds (EC$_{50}$Tooltip half-maximal effective concentration, nM) :
| Compound | 5-HTTooltip Serotonin | NETooltip Norepinephrine | DATooltip Dopamine | Type | Class |
| Tryptamine | 32.6 | 716 | 164 | SDRA | Tryptamine |
| α-Methyltryptamine (αMT) | 21.7–68 | 79–112 | 78.6–180 | SNDRA | Tryptamine |
| α-Ethyltryptamine (αET) | 23.2 | 640 | 232 | SDRA | Tryptamine |
| (–)-αET | 54.9 | 3670$^a$ | 654 | SRA | Tryptamine |
| (+)-αET | 34.7 | 592$^a$ | 57.6 | SDRA | Tryptamine |
| 5-Fluoro-αMT | 19 | 126 | 32 | SNDRA | Tryptamine |
| 5-Chloro-αMT | 16 | 3434 | 54 | SDRA | Tryptamine |
| 5-Fluoro-αET | 36.6 | 5334 | 150 | SDRA | Tryptamine |
| 5-MeO-αMT | 460 | 8900 | 1500 | SNDRA | Tryptamine |
| BK-NM-AMT | 41.3 | ND (55% at 10 μM) | 92.8 | SDRA | Tryptamine |
| BK-5F-NM-AMT | 190 | ND | 620 | ND | Tryptamine |
| BK-5Cl-NM-AMT | 200 | ND | 865 | ND | Tryptamine |
| BK-5Br-NM-AMT | 295 | ND | 2100 | ND | Tryptamine |
| 3-Methoxymethcathinone (3-MeOMC) | 306 | 111 (68% at 10 μM) | 129 | SDRA/SNDRA | Cathinone |
| Notes: The smaller the value, the more strongly the substance releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Footnotes: $^a$ = αET, (–)-αET, and (+)-αET were norepinephrine partial releasers with E$_{max}$ values of 78%, 75%, and 71%, respectively. |||||||