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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.

A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI).

Examples of SDRAs

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.^[2] 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-HT_2A 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.^[3]

Another tryptamine SDRA is BK-NM-AMT (α,N-dimethyl-β-ketotryptamine).^[3]^[4]^[5] It is the N-methyl and β-keto analogue of αMT.^[3]^[4]^[5] The drug is a cathinone-like tryptamine and can be thought of as the tryptamine analogue of methcathinone.^[3]^[4] Its EC₅₀Tooltip 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.^[3] BK-NM-AMT has been described in a patent assigned to Tactogen and published in October 2024.^[5]^[4] 5-Halogenated derivatives of this drug, including BK-5F-NM-AMT,^[6]^[7] BK-5Cl-NM-AMT,^[8]^[9] and BK-5Br-NM-AMT,^[10]^[11] have also been described and patented.^[12] Like BK-NM-AMT, they induce serotonin and dopamine release.^[12] 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.^[12] In addition, unlike other α-alkyltryptamines like αMT, they are inactive as monoamine oxidase inhibitors (MAOIs).^[12]

3-Methoxymethcathinone (3-MeOMC) is a rare possible example of a phenethylamine (or rather cathinone) SDRA.^[3] Its EC₅₀Tooltip 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.^[3] However, in another publication, its EC₅₀ for induction of norepinephrine release was reported and was 111 nM.^[13]^[14]

Activity profiles

Activity profiles of SDRAs and related compounds (EC₅₀Tooltip half-maximal effective concentration, nM)
Compound	5-HTTooltip Serotonin	NETooltip Norepinephrine	DATooltip Dopamine	Type	Class	Ref
Tryptamine	32.6	716	164	SDRA	Tryptamine	^[15]^[1]
α-Methyltryptamine (αMT)	21.7–68	79–112	78.6–180	SNDRA	Tryptamine	^[16]^[1]
α-Ethyltryptamine (αET)	23.2	640	232	SDRA	Tryptamine	^[1]
5-Fluoro-αMT	19	126	32	SNDRA	Tryptamine	^[17]
5-Chloro-αMT	16	3434	54	SDRA	Tryptamine	^[1]^[17]
5-Fluoro-αET	36.6	5334	150	SDRA	Tryptamine	^[1]
5-MeO-αMT	460	8900	1500	SNDRA	Tryptamine	^[16]
BK-NM-AMT	41.3	ND (55% at 10 μM)	92.8	SDRA	Tryptamine	^[3]^[5]
BK-5F-NM-AMT	190	ND	620	ND	Tryptamine	^[12]
BK-5Cl-NM-AMT	200	ND	865	ND	Tryptamine	^[12]
BK-5Br-NM-AMT	295	ND	2100	ND	Tryptamine	^[12]
3-Methoxymethcathinone (3-MeOMC)	306	111 (68% at 10 μM)	129	SDRA/SNDRA	Cathinone	^[3]^[13]^[14]
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.