serotonin–dopamine releasing agent

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.{{cite journal | vauthors = Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, Negus SS | title = Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys | journal = Experimental and Clinical Psychopharmacology | volume = 22 | issue = 3 | pages = 274–284 | date = June 2014 | pmid = 24796848 | pmc = 4067459 | doi = 10.1037/a0036595 }} 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-HT_2A 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).{{cite journal | vauthors = Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB | title = The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes | journal = Psychopharmacology | volume = 236 | issue = 3 | pages = 915–924 | date = March 2019 | pmid = 30341459 | pmc = 6475490 | doi = 10.1007/s00213-018-5063-9 }}{{cite web | title=1-(1H-indol-3-yl)-2-(methylamino)propan-1-one | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/82282492 | access-date=11 November 2024}} 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 {{Abbrlink|EC₅₀|half-maximal effective concentration}} values for monoamine release are 41.3{{nbsp}}nM for serotonin and 92.8{{nbsp}}nM for dopamine, whereas it only induced 55% release of norepinephrine at a concentration of 10{{nbsp}}μM. BK-NM-AMT has been described in a patent filed by Matthew Baggott, assigned to Tactogen, and published in October 2024.{{cite patent | country = US | number = 20240335414 | invent1 = Matthew J. Baggott | invent2 = Sean Dalziel | assign = Tactogen Inc. | title=Specialized combinations for mental disorders or mental enhancement | url=https://patents.google.com/patent/US20240335414A1/ | pubdate = 10 October 2024 }} 5-Halogenated derivatives of this drug, including BK-5F-NM-AMT,{{cite web | title=1-(5-fluoro-1H-indol-3-yl)-2-(methylamino)propan-1-one | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/162765676 | access-date=11 November 2024}}{{cite web | title=β-Oxo-5-fluoro-α-methyl-NMT | website=Isomer Design | date=10 November 2024 | url=https://isomerdesign.com/pihkal/explore/12714 | access-date=11 November 2024}} BK-5Cl-NM-AMT,{{cite web | title=1-(5-chloro-1H-indol-3-yl)-2-(methylamino)propan-1-one | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/162765502 | access-date=11 November 2024}}{{cite web | title=β-Oxo-5-chloro-α-methyl-NMT | website=Isomer Design | date=10 November 2024 | url=https://isomerdesign.com/pihkal/explore/12715 | access-date=11 November 2024}} and BK-5Br-NM-AMT,{{cite web | title=1-(5-bromo-1H-indol-3-yl)-2-(methylamino)propan-1-one | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/162765532 | access-date=11 November 2024}}{{cite web | title=β-Oxo-5-bromo-α-methyl-NMT | website=Isomer Design | date=10 November 2024 | url=https://isomerdesign.com/pihkal/explore/12725 | access-date=11 November 2024}} have also been described and patented.{{cite patent | country = WO | number = 2022061242 | inventor = Matthew Baggott | status = | title = Advantageous tryptamine compositions for mental disorders or enhancement | pubdate = 2023 March 24 | gdate = | fdate = 2021 September 20 | pridate = 2021 September 20 | assign1 = Tactogen | url = https://patents.google.com/patent/WO2022061242A1/}} 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 {{Abbrlink|EC₅₀|half-maximal effective concentration}} values for monoamine release are 129{{nbsp}}nM for dopamine and 306{{nbsp}}nM for serotonin, whereas it only induced 68% release of norepinephrine at 10{{nbsp}}μM. However, in another publication, its {{Abbr|EC₅₀|half-maximal effective concentration}} for induction of norepinephrine release was reported and was 111{{nbsp}}nM.{{cite thesis | last=Shalabi | first=Abdelrahman R. | title=Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters | website=VCU Scholars Compass | date=14 December 2017 | doi=10.25772/M4E1-3549 | url=https://scholarscompass.vcu.edu/etd/5176/ | access-date=24 November 2024}}{{cite journal | vauthors = Walther D, Shalabi AR, Baumann MH, Glennon RA | title = Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents | journal = ACS Chem Neurosci | volume = 10 | issue = 1 | pages = 740–745 | date = January 2019 | pmid = 30354055 | pmc = 8269283 | doi = 10.1021/acschemneuro.8b00524 | url = }}

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.{{cite journal | vauthors = Guajardo FG, Velásquez VB, Raby D, Núñez-Vivanco G, Iturriaga-Vásquez P, España RA, Reyes-Parada M, Sotomayor-Zárate R | title = Pharmacological Characterization of 4-Methylthioamphetamine Derivatives | journal = Molecules | volume = 25 | issue = 22 | date = November 2020 | page = 5310 | pmid = 33203055 | pmc = 7696343 | doi = 10.3390/molecules25225310 | doi-access = free | url = }}{{cite journal | vauthors = 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 | title = Improving amphetamine therapeutic selectivity: N,N-dimethyl-MTA has dopaminergic effects and does not produce aortic contraction | journal = Basic Clin Pharmacol Toxicol | volume = 114 | issue = 5 | pages = 395–399 | date = May 2014 | pmid = 24314229 | doi = 10.1111/bcpt.12168 | url = }}{{cite journal | vauthors = 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 | title = 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 | journal = J Neurochem | volume = 105 | issue = 5 | pages = 1770–1780 | date = June 2008 | pmid = 18248615 | pmc = 4502523 | doi = 10.1111/j.1471-4159.2008.05272.x | url = }} However, {{Abbr|EC₅₀|half-maximal effective concentration}} 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 {{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} of 2,100{{nbsp}}nM.{{cite journal | vauthors = Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK | title = Amphetamine Derivatives as Monoamine Oxidase Inhibitors | journal = Front Pharmacol | volume = 10 | issue = | pages = 1590 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | url = }}

{{Main|Monoamine releasing agent#Mechanism of action}}

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

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{{Monoamine releasing agents}}

{{DEFAULTSORT:Serotonin-dopamine releasing agent}}

Category:Serotonin-dopamine releasing agents