Serotonin–dopamine releasing agent explained

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, owing to the fact that it has proven extremely difficult to dissociate dopamine and norepinephrine release.[1] [2] 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).[3] [4] [5]

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.[6] 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).[7] [8] 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.[9] 5-Halogenated derivatives of this drug, including BK-5F-NM-AMT,[10] [11] BK-5Cl-NM-AMT,[12] [13] and BK-5Br-NM-AMT,[14] [15] have also been described and patented.[16] 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.[17] [18]

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.[19] [20] [21] 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.[22]

Activity profiles

Activity profiles of SDRAs and related compounds (nM)
Compound data-sort-type="number" !data-sort-type="number" !data-sort-type="number" !Type Class Ref
32.6 716 164 SDRA Tryptamine [23] [24]
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
19 126 32 SNDRA Tryptamine [25]
16 3434 54 SDRA Tryptamine
36.6 5334 150 SDRA Tryptamine
460 8900 1500 SNDRA Tryptamine [26]
41.3 (55% at 10μM) 92.8 SDRA Tryptamine
190 620 Tryptamine
200 865 Tryptamine
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.

See also

Notes and References

  1. Rothman RB, Blough BE, Baumann MH . Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions . AAPS J . 9 . 1 . E1–10 . January 2007 . 17408232 . 2751297 . 10.1208/aapsj0901001 . Based in part on the above rationale, we sought to identify and characterize a non-amphetamine transporter substrate that would be a potent releaser of DA and 5-HT without affecting the release of NE. After an extensive evaluation of over 350 compounds, we found it virtually impossible to dissociate NE-and DA-releasing properties, perhaps because of phylogenetic similarities between NET and DAT..
  2. Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB . 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 . 320 . 2 . 627–636 . February 2007 . 17071819 . 10.1124/jpet.106.107383 . As is commonly true for existing monoamine releasers, the potency of these compounds to release norepinephrine was similar to or higher than potency to release dopamine, and compounds with exclusive selectivity for dopamine or norepinephrine release are not yet available (Rothman et al., 2001). [...] Second, the present study documented optimal effects with releasers selective for dopamine/norepinephrine versus serotonin release; however, the degree to which the dopaminergic and/or noradrenergic effects of these drugs contributes to their profiles of behavioral effects remains to be determined. Releasers with selectivity for dopamine versus both norepinephrine and serotonin would help address this issue..
  3. Huot P, Fox SH, Brotchie JM . Monoamine reuptake inhibitors in Parkinson's disease . Parkinsons Dis . 2015 . 609428 . 2015 . 25810948 . 4355567 . 10.1155/2015/609428 . free .
  4. Huot P, Fox SH, Brotchie JM . Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of Nonhuman Primate Studies and Clinical Trials . J Pharmacol Exp Ther . 357 . 3 . 562–569 . June 2016 . 27190169 . 10.1124/jpet.116.232371 .
  5. Johnston TH, Millar Z, Huot P, Wagg K, Thiele S, Salomonczyk D, Yong-Kee CJ, Gandy MN, McIldowie M, Lewis KD, Gomez-Ramirez J, Lee J, Fox SH, Martin-Iverson M, Nash JE, Piggott MJ, Brotchie JM . A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates . FASEB J . 26 . 5 . 2154–2163 . May 2012 . 22345403 . 10.1096/fj.11-195016 . free .
  6. Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, Negus SS . Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys . Experimental and Clinical Psychopharmacology . 22 . 3 . 274–284 . June 2014 . 24796848 . 4067459 . 10.1037/a0036595 .
  7. Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB . The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes . Psychopharmacology . 236 . 3 . 915–924 . March 2019 . 30341459 . 6475490 . 10.1007/s00213-018-5063-9 .
  8. Web site: 1-(1H-indol-3-yl)-2-(methylamino)propan-1-one . PubChem . 11 November 2024.
  9. Web site: Specialized combinations for mental disorders or mental enhancement . Google Patents . 7 June 2024 . 4 November 2024.
  10. Web site: 1-(5-fluoro-1H-indol-3-yl)-2-(methylamino)propan-1-one . PubChem . 11 November 2024.
  11. Web site: β-Oxo-5-fluoro-α-methyl-NMT . Isomer Design . 10 November 2024 . 11 November 2024.
  12. Web site: 1-(5-chloro-1H-indol-3-yl)-2-(methylamino)propan-1-one . PubChem . 11 November 2024.
  13. Web site: β-Oxo-5-chloro-α-methyl-NMT . Isomer Design . 10 November 2024 . 11 November 2024.
  14. Web site: 1-(5-bromo-1H-indol-3-yl)-2-(methylamino)propan-1-one . PubChem . 11 November 2024.
  15. Web site: β-Oxo-5-bromo-α-methyl-NMT . Isomer Design . 10 November 2024 . 11 November 2024.
  16. Web site: Advantageous tryptamine compositions for mental disorders or enhancement . Google Patents . 20 September 2021 . 11 November 2024.
  17. Shalabi . Abdelrahman R. . Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters . VCU Scholars Compass . 14 December 2017 . 10.25772/M4E1-3549 . 24 November 2024.
  18. Walther D, Shalabi AR, Baumann MH, Glennon RA . Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents . ACS Chem Neurosci . 10 . 1 . 740–745 . January 2019 . 30354055 . 8269283 . 10.1021/acschemneuro.8b00524 .
  19. Guajardo FG, Velásquez VB, Raby D, Núñez-Vivanco G, Iturriaga-Vásquez P, España RA, Reyes-Parada M, Sotomayor-Zárate R . Pharmacological Characterization of 4-Methylthioamphetamine Derivatives . Molecules . 25 . 22 . November 2020 . 5310 . 33203055 . 7696343 . 10.3390/molecules25225310 . free .
  20. Sotomayor-Zárate R, Jara P, Araos P, Vinet R, Quiroz G, Renard GM, Espinosa P, Hurtado-Guzmán C, Moya PR, Iturriaga-Vásquez P, Gysling K, Reyes-Parada M . Improving amphetamine therapeutic selectivity: N,N-dimethyl-MTA has dopaminergic effects and does not produce aortic contraction . Basic Clin Pharmacol Toxicol . 114 . 5 . 395–399 . May 2014 . 24314229 . 10.1111/bcpt.12168 .
  21. Gobbi M, Funicello M, Gerstbrein K, Holy M, Moya PR, Sotomayor R, Forray MI, Gysling K, Paluzzi S, Bonanno G, Reyes-Parada M, Sitte HH, Mennini T . 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 . 105 . 5 . 1770–1780 . June 2008 . 18248615 . 4502523 . 10.1111/j.1471-4159.2008.05272.x .
  22. Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK . Amphetamine Derivatives as Monoamine Oxidase Inhibitors . Front Pharmacol . 10 . 1590 . 2019 . 32038257 . 6989591 . 10.3389/fphar.2019.01590 . free .
  23. Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB . Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes . Psychopharmacology . 231 . 21 . 4135–4144 . October 2014 . 24800892 . 4194234 . 10.1007/s00213-014-3557-7 .
  24. Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB . Alpha-ethyltryptamines as dual dopamine-serotonin releasers . Bioorganic & Medicinal Chemistry Letters . 24 . 19 . 4754–4758 . October 2014 . 25193229 . 4211607 . 10.1016/j.bmcl.2014.07.062 .
  25. Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, Negus SS . Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys . Experimental and Clinical Psychopharmacology . 22 . 3 . 274–284 . June 2014 . 24796848 . 4067459 . 10.1037/a0036595 .
  26. Nagai F, Nonaka R, Satoh Hisashi Kamimura K . The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain . European Journal of Pharmacology . 559 . 2–3 . 132–137 . March 2007 . 17223101 . 10.1016/j.ejphar.2006.11.075 .

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