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. A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI).

Examples of SDRAs

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.[2] 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.[3] Another tryptamine SDRA is BK-NM-AMT (α,N-dimethyl-β-ketotryptamine).[3][4][5] It is the N-methyl and β-keto analogue of αMT.[3][4][5] The drug is a cathinone-like tryptamine and can be thought of as the tryptamine analogue of methcathinone.[3][4] 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.[3] BK-NM-AMT has been described in a patent assigned to Tactogen and published in October 2024.[5][4] 5-Halogenated derivatives of this drug, including BK-5F-NM-AMT,[6][7] BK-5Cl-NM-AMT,[8][9] and BK-5Br-NM-AMT,[10][11] have also been described and patented.[12] Like BK-NM-AMT, they induce serotonin and dopamine release.[12] 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.[12] In addition, unlike other α-alkyltryptamines like αMT, they are inactive as monoamine oxidase inhibitors (MAOIs).[12] 3-Methoxymethcathinone (3-MeOMC) is a rare possible example of a phenethylamine (or rather cathinone) SDRA.[3] 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.[3] However, in another publication, its EC50 for induction of norepinephrine release was reported and was 111 nM.[13][14]

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 [15][1]
α-Methyltryptamine (αMT) 21.7–68 79–112 78.6–180 SNDRA Tryptamine [16][1]
α-Ethyltryptamine (αET) 23.2 640 232 SDRA Tryptamine [1]
5-Fluoro-αMT 19 126 32 SNDRA Tryptamine [17]
5-Chloro-αMT 16 3434 54 SDRA Tryptamine [1][17]
5-Fluoro-αET 36.6 5334 150 SDRA Tryptamine [1]
5-MeO-αMT 460 8900 1500 SNDRA Tryptamine [16]
BK-NM-AMT 41.3 ND (55% at 10 μM) 92.8 SDRA Tryptamine [3][5]
BK-5F-NM-AMT 190 ND 620 ND Tryptamine [12]
BK-5Cl-NM-AMT 200 ND 865 ND Tryptamine [12]
BK-5Br-NM-AMT 295 ND 2100 ND Tryptamine [12]
3-Methoxymethcathinone (3-MeOMC) 306 111 (68% at 10 μM) 129 SDRA/SNDRA Cathinone [3][13][14]
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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 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. ↑ 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.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 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.
  4. ↑ 4.0 4.1 4.2 4.3 "1-(1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  5. ↑ 5.0 5.1 5.2 5.3 "Specialized combinations for mental disorders or mental enhancement". Google Patents. 7 June 2024. Retrieved 4 November 2024.
  6. ↑ "1-(5-fluoro-1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  7. ↑ "β-Oxo-5-fluoro-α-methyl-NMT". Isomer Design. 10 November 2024. Retrieved 11 November 2024.
  8. ↑ "1-(5-chloro-1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  9. ↑ "β-Oxo-5-chloro-α-methyl-NMT". Isomer Design. 10 November 2024. Retrieved 11 November 2024.
  10. ↑ "1-(5-bromo-1H-indol-3-yl)-2-(methylamino)propan-1-one". PubChem. Retrieved 11 November 2024.
  11. ↑ "β-Oxo-5-bromo-α-methyl-NMT". Isomer Design. 10 November 2024. Retrieved 11 November 2024.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 "Advantageous tryptamine compositions for mental disorders or enhancement". Google Patents. 20 September 2021. Retrieved 11 November 2024.
  13. ↑ 13.0 13.1 Shalabi AR (14 December 2017). "Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters". VCU Scholars Compass. Retrieved 24 November 2024.
  14. ↑ 14.0 14.1 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.
  15. ↑ 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ 17.0 17.1 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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