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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.[1]
SDRAs are rare, owing to the fact that it has proven extremely difficult to dissociate dopamine and norepinephrine release.[2][3] However, in 2014, the first selective SDRAs, a series of substituted tryptamines, albeit also acting as serotonin receptor agonists, were described.[1]
A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI), for instance UWA-101 (α-cyclopropyl-MDMA).[4][5][6]
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A number of tryptamine derivatives have been found to act as SDRAs.[1] 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.[7] 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.[1] 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-HT2A receptor, and are likely to act as agonists of other serotonin receptors as well.[1] In any case, they are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine.[8]
Another tryptamine SDRA is BK-NM-AMT (α,N-dimethyl-β-ketotryptamine).[8][9][10] It is the N-methyl and β-keto analogue of αMT.[8][9][10] The drug is a cathinone-like tryptamine and can be thought of as the tryptamine analogue of methcathinone.[8][9] Its EC50 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.[8] BK-NM-AMT has been described in a patent assigned to Tactogen and published in October 2024.[10][9] 5-Halogenated derivatives of this drug, including BK-5F-NM-AMT,[11][12] BK-5Cl-NM-AMT,[13][14] and BK-5Br-NM-AMT,[15][16] have also been described and patented.[17] Like BK-NM-AMT, they induce serotonin and dopamine release.[17] In contrast to many other tryptamines, these compounds are inactive as agonists of serotonin receptors including the 5-HT1, 5-HT2, and 5-HT3 receptors.[17] In addition, unlike other α-alkyltryptamines like αMT, they are inactive as monoamine oxidase inhibitors (MAOIs).[17]
3-Methoxymethcathinone (3-MeOMC) is a rare possible example of a phenethylamine (or rather cathinone) SDRA.[8] Its EC50 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.[8] However, in another publication, its EC50 for induction of norepinephrine release was reported and was 111 nM.[18][19]
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.[20][21][22] However, EC50 values for monoamine release were not reported.[21][22] 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).[22] Although 4-MTDMA might not induce norepinephrine release, it is a monoamine oxidase A (MAO-A) inhibitor, with an IC50 of 2,100 nM.[23]
Activity profiles
| Compound | 5-HT | NE | DA | Type | Class | Ref |
|---|---|---|---|---|---|---|
| Tryptamine | 32.6 | 716 | 164 | SDRA | Tryptamine | [24][1] |
| α-Methyltryptamine (αMT) | 21.7–68 | 79–112 | 78.6–180 | SNDRA | Tryptamine | [25][1] |
| α-Ethyltryptamine (αET) | 23.2 | 640 | 232 | SDRA | Tryptamine | [1] |
| 5-Fluoro-αMT | 19 | 126 | 32 | SNDRA | Tryptamine | [26] |
| 5-Chloro-αMT | 16 | 3434 | 54 | SDRA | Tryptamine | [1][26] |
| 5-Fluoro-αET | 36.6 | 5334 | 150 | SDRA | Tryptamine | [1] |
| 5-MeO-αMT | 460 | 8900 | 1500 | SNDRA | Tryptamine | [25] |
| BK-NM-AMT | 41.3 | ND (55% at 10 μM) | 92.8 | SDRA | Tryptamine | [8][10] |
| BK-5F-NM-AMT | 190 | ND | 620 | ND | Tryptamine | [17] |
| BK-5Cl-NM-AMT | 200 | ND | 865 | ND | Tryptamine | [17] |
| BK-5Br-NM-AMT | 295 | ND | 2100 | ND | Tryptamine | [17] |
| 3-Methoxymethcathinone (3-MeOMC) | 306 | 111 (68% at 10 μM) | 129 | SDRA/SNDRA | Cathinone | [8][18][19] |
| 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. | ||||||
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