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Serotonin–dopamine releasing agent

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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.[1]

SDRAs are rare, owing to the fact that it has proven extremely difficult to dissociate dopamine and norepinephrine release.[2][3] However, in 2014, the first selective SDRAs, a series of substituted tryptamines, albeit also acting as serotonin receptor agonists, were described.[1]

A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI), for instance UWA-101 (α-cyclopropyl-MDMA).[4][5][6]

Examples of SDRAs

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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.[7] 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-HT2A 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.[8]

Another tryptamine SDRA is BK-NM-AMT (α,N-dimethyl-β-ketotryptamine).[8][9][10] It is the N-methyl and β-keto analogue of αMT.[8][9][10] The drug is a cathinone-like tryptamine and can be thought of as the tryptamine analogue of methcathinone.[8][9] 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.[8] BK-NM-AMT has been described in a patent assigned to Tactogen and published in October 2024.[10][9] 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.[8] 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.[8] 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

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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][1]
α-Methyltryptamine (αMT) 21.7–68 79–112 78.6–180 SNDRA Tryptamine [25][1]
α-Ethyltryptamine (αET) 23.2 640 232 SDRA Tryptamine [1]
5-Fluoro-αMT 19 126 32 SNDRA Tryptamine [26]
5-Chloro-αMT 16 3434 54 SDRA Tryptamine [1][26]
5-Fluoro-αET 36.6 5334 150 SDRA Tryptamine [1]
5-MeO-αMT 460 8900 1500 SNDRA Tryptamine [25]
BK-NM-AMT 41.3 ND (55% at 10 μM) 92.8 SDRA Tryptamine [8][10]
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 [8][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.

See also

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References

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  1. ^ a b c d e f g h i j Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–4758. doi:10.1016/j.bmcl.2014.07.062. PMC 4211607. PMID 25193229.
  2. ^ Rothman RB, Blough BE, Baumann MH (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". AAPS J. 9 (1): E1–10. doi:10.1208/aapsj0901001. PMC 2751297. PMID 17408232. 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.
  3. ^ Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB (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. 320 (2): 627–636. doi:10.1124/jpet.106.107383. PMID 17071819. 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.
  4. ^ Huot P, Fox SH, Brotchie JM (2015). "Monoamine reuptake inhibitors in Parkinson's disease". Parkinsons Dis. 2015: 609428. doi:10.1155/2015/609428. PMC 4355567. PMID 25810948.
  5. ^ Huot P, Fox SH, Brotchie JM (June 2016). "Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of Nonhuman Primate Studies and Clinical Trials". J Pharmacol Exp Ther. 357 (3): 562–569. doi:10.1124/jpet.116.232371. PMID 27190169.
  6. ^ Johnston TH, Millar Z, Huot P, Wagg K, Thiele S, Salomonczyk D, et al. (May 2012). "A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates". FASEB J. 26 (5): 2154–2163. doi:10.1096/fj.11-195016. PMID 22345403.
  7. ^ Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, et al. (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. 22 (3): 274–284. doi:10.1037/a0036595. PMC 4067459. PMID 24796848.
  8. ^ a b c d e f g h i Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, et al. (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology. 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC 6475490. PMID 30341459.
  9. ^ a b c d "1-(1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  10. ^ a b c d "Specialized combinations for mental disorders or mental enhancement". Google Patents. 7 June 2024. Retrieved 4 November 2024.
  11. ^ "1-(5-fluoro-1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  12. ^ "β-Oxo-5-fluoro-α-methyl-NMT". Isomer Design. 10 November 2024. Retrieved 11 November 2024.
  13. ^ "1-(5-chloro-1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  14. ^ "β-Oxo-5-chloro-α-methyl-NMT". Isomer Design. 10 November 2024. Retrieved 11 November 2024.
  15. ^ "1-(5-bromo-1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  16. ^ "β-Oxo-5-bromo-α-methyl-NMT". Isomer Design. 10 November 2024. Retrieved 11 November 2024.
  17. ^ a b c d e f g "Advantageous tryptamine compositions for mental disorders or enhancement". Google Patents. 20 September 2021. Retrieved 11 November 2024.
  18. ^ a b Shalabi AR (14 December 2017). Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters. VCU Scholars Compass (Thesis). doi:10.25772/M4E1-3549. Retrieved 24 November 2024.
  19. ^ a b Walther D, Shalabi AR, Baumann MH, Glennon RA (January 2019). "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. doi:10.1021/acschemneuro.8b00524. PMC 8269283. PMID 30354055.
  20. ^ Guajardo FG, Velásquez VB, Raby D, Núñez-Vivanco G, Iturriaga-Vásquez P, España RA, et al. (November 2020). "Pharmacological Characterization of 4-Methylthioamphetamine Derivatives". Molecules. 25 (22): 5310. doi:10.3390/molecules25225310. PMC 7696343. PMID 33203055.
  21. ^ a b Sotomayor-Zárate R, Jara P, Araos P, Vinet R, Quiroz G, Renard GM, et al. (May 2014). "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. doi:10.1111/bcpt.12168. PMID 24314229.
  22. ^ a b c Gobbi M, Funicello M, Gerstbrein K, Holy M, Moya PR, Sotomayor R, et al. (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. 105 (5): 1770–1780. doi:10.1111/j.1471-4159.2008.05272.x. PMC 4502523. PMID 18248615.
  23. ^ Cite error: The named reference Reyes-ParadaIturriaga-VasquezCassels2019 was invoked but never defined (see the help page).
  24. ^ Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology. 231 (21): 4135–4144. doi:10.1007/s00213-014-3557-7. PMC 4194234. PMID 24800892.
  25. ^ a b Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
  26. ^ a b Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, et al. (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. 22 (3): 274–284. doi:10.1037/a0036595. PMC 4067459. PMID 24796848.
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