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, as 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-HT2A 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 values for monoamine release are 41.3nM for serotonin and 92.8nM for dopamine, whereas it only induced 55% release of norepinephrine at a concentration of 10μM. 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-HT1, 5-HT2, and 5-HT3 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 values for monoamine release are 129nM for dopamine and 306nM for serotonin, whereas it only induced 68% release of norepinephrine at 10μM. However, in another publication, its for induction of norepinephrine release was reported and was 111nM.

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, 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 of 2,100nM.

Activity profiles + Activity profiles of SDRAs and related compounds (, nM) Compound Type Class Ref 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 3670a 654 SRA Tryptamine (+)-αET 34.7 592a 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 (55% at 10μM) 92.8 SDRA Tryptamine BK-5F-NM-AMT 190 620 Tryptamine BK-5Cl-NM-AMT 200 865 Tryptamine BK-5Br-NM-AMT 295 2100 Tryptamine 3-Methoxymethcathinone (3-MeOMC) 306 111 (68% at 10μM) 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 Emax values of 78%, 75%, and 71%, respectively.

Mechanism of action

See also Monoamine releasing agent Serotonin releasing agent Dopamine releasing agent Serotonin–norepinephrine–dopamine releasing agent

References