Serotonin–dopamine releasing agent

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 EC50 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, EC50 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

Mechanism of action

Main article: Monoamine releasing agent#Mechanism of action

References

References

1. (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". AAPS J.
2. (February 2007). "Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys". J Pharmacol Exp Ther.
3. (2015). "Monoamine reuptake inhibitors in Parkinson's disease". Parkinsons Dis.
4. (June 2016). "Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of Nonhuman Primate Studies and Clinical Trials". J Pharmacol Exp Ther.
5. (May 2012). "A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates". FASEB J.
6. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology.
7. (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology.
8. "1-(1H-indol-3-yl)-2-(methylamino)propan-1-one".
9. "Specialized combinations for mental disorders or mental enhancement".
10. "1-(5-fluoro-1H-indol-3-yl)-2-(methylamino)propan-1-one".
11. (10 November 2024). "β-Oxo-5-fluoro-α-methyl-NMT".
12. "1-(5-chloro-1H-indol-3-yl)-2-(methylamino)propan-1-one".
13. (10 November 2024). "β-Oxo-5-chloro-α-methyl-NMT".
14. "1-(5-bromo-1H-indol-3-yl)-2-(methylamino)propan-1-one".
15. (10 November 2024). "β-Oxo-5-bromo-α-methyl-NMT".
16. "Advantageous tryptamine compositions for mental disorders or enhancement".
17. Shalabi, Abdelrahman R.. (14 December 2017). "Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters".
18. (January 2019). "Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents". ACS Chem Neurosci.
19. (November 2020). "Pharmacological Characterization of 4-Methylthioamphetamine Derivatives". Molecules.
20. (May 2014). "Improving amphetamine therapeutic selectivity: N,N-dimethyl-MTA has dopaminergic effects and does not produce aortic contraction". Basic Clin Pharmacol Toxicol.
21. (June 2008). "N,N-dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currents". J Neurochem.
22. (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol.
23. (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology.
24. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters.
25. (June 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology.
26. (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology.