Serotonin–dopamine releasing agent

Further information: serotonin releasing agent and 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.^[3]

BK-NM-AMT, a well-balanced and selective SDRA.^[1][2]

SDRAs are rare, owing to the fact that it has proven extremely difficult to dissociate dopamine and norepinephrine release.^[4][5] However, in 2014, the first selective SDRAs, a series of substituted tryptamines, albeit also acting as serotonin receptor agonists, were described.^[3]

A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI), for instance UWA-101 (α-cyclopropyl-MDMA).^[6][7][8]

Examples of SDRAs

A number of tryptamine derivatives, specifically α-alkyltryptamines, have been found to act as SDRAs.^[3] 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.^[9] 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.^[3] 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.^[3] In any case, they are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine.^[1]

Another tryptamine SDRA is the β-ketotryptamine BK-NM-AMT (α,N-dimethyl-β-ketotryptamine).^[1][10][2] It is the N-methyl and β-keto analogue of αMT.^[1][10][2] The drug is a cathinone-like tryptamine and can be thought of as the tryptamine analogue of methcathinone.^[1][10] 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.^[1] BK-NM-AMT has been described in a patent filed by Matthew Baggott, assigned to Tactogen, and published in October 2024.^[2][10] 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.^[1] 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.^[1] 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 IC₅₀Tooltip half-maximal inhibitory concentration of 2,100 nM.^[23]

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	[24][3]
α-Methyltryptamine (αMT)	21.7–68	79–112	78.6–180	SNDRA	Tryptamine	[25][3]
α-Ethyltryptamine (αET)	23.2	640	232	SDRA	Tryptamine	[3]
(–)-αET	54.9	3670a	654	SRA	Tryptamine	[3]
(+)-αET	34.7	592a	57.6	SDRA	Tryptamine	[3]
5-Fluoro-αMT	19	126	32	SNDRA	Tryptamine	[26]
5-Chloro-αMT	16	3434	54	SDRA	Tryptamine	[3][26]
5-Fluoro-αET	36.6	5334	150	SDRA	Tryptamine	[3]
5-MeO-αMT	460	8900	1500	SNDRA	Tryptamine	[25]
BK-NM-AMT	41.3	ND (55% at 10 μM)	92.8	SDRA	Tryptamine	[1][2]
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	[1][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. Footnotes: a = αET, (–)-αET, and (+)-αET were norepinephrine partial releasers with Emax values of 78%, 75%, and 71%, respectively.

Mechanism of action

Main article: Monoamine releasing agent § Mechanism of action

See also

• Monoamine releasing agent
• Serotonin releasing agent
• Dopamine releasing agent
• Serotonin–norepinephrine–dopamine releasing agent