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Dopamine releasing agent

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Amphetamine, an NDRA and one of the most well-known DRAs.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.[1][2][3][4]

No selective DRAs are currently known.[5][6] However, non-selective DRAs, including norepinephrine–dopamine releasing agents (NDRAs) like amphetamine and methamphetamine, serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like MDMA and mephedrone, and serotonin–dopamine releasing agents (SDRAs) like 5-chloro-αMT are known.[7][8][9]

A closely related type of drug is a dopamine reuptake inhibitor (DRI).[10][11][12] In contrast to the case of DRAs, many selective DRIs are known.[10][11][12] Examples of selective DRIs include amineptine, modafinil, and vanoxerine.[10][11][12]

Selectivity

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No selective and robust DRAs are currently known.[5][6] The lack of selective DRAs as of present is related to the fact that it has proven extremely difficult to separate dopamine transporter (DAT) affinity from norepinephrine transporter (NET) affinity and retain releasing capability at the same time.[6] Despite extensive evaluation of over 350 compounds, it was reported in 2007 that it had been virtually impossible to dissociate norepinephrine and dopamine release.[6] This was attributed to the strong phylogenetic similarities between the DAT and NET.[6] However, selective SDRAs, albeit with concomitant serotonin receptor agonism, were subsequently described in 2014, though selective DRAs were still not reported.[9]

Although no selective DRAs are currently known, many non-selective releasing agents of both dopamine and norepinephrine (norepinephrine–dopamine releasing agents or NDRAs) and of serotonin, norepinephrine, and dopamine (serotonin–norepinephrine–dopamine releasing agents or SNDRAs) are known.[7][8] Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA).[7][8] These drugs are frequently used for recreational purposes and encountered as drugs of abuse. DRAs, including NDRAs and theoretically also selective DRAs, have medical utility in the treatment of attention deficit hyperactivity disorder (ADHD).[13] Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are less common and are not selective for dopamine release, but have also been developed.[9][14] Tryptamines like 5-chloro-αMT are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine.[15]

Therapeutic applications

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Selective DRAs might have different clinical effects in the treatment of attention deficit hyperactivity disorder (ADHD) than the NDRAs like amphetamines and norepinephrine–dopamine reuptake inhibitors (NDRIs) like methylphenidate that are currently used.[13] For example, they might have improved therapeutic selectivity by reducing or eliminating the cardiovascular and sympathomimetic side effects of NDRAs.[16]

Examples of DRAs

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Dextromethamphetamine is one of the most selective known releasers of dopamine over norepinephrine, but it is still fairly balanced as an NDRA.[7][8] Another of the most specific dopamine releasers is recreational stimulant cis-4-methylaminorex (cis-4-MAR), but it also has considerable activity as a norepinephrine releaser and hence is likewise not a selective DRA.[17][18] Pemoline, which is structurally related to the aminorex drugs, is a stimulant used to treat ADHD which is said to act as a selective DRI and DRA, but it only weakly stimulates dopamine release.[19][20][21]

There is reportedly some, albeit mixed, in-vitro evidence that the antidepressant and modestly selective DRI amineptine may, in addition to inhibiting the reuptake of dopamine, selectively induce the presynaptic release of dopamine without affecting release of norepinephrine or serotonin.[22][23][24] However, amineptine is larger than the known small structural size limit of monoamine releasing agents, suggesting that it may not in fact be a DRA.[3]

Although no definite selective DRAs have been described, one possible exception is 2-fluoromethcathinone (2-FMC).[15] It has an EC50Tooltip half-maximal effective concentration for dopamine release of 48.7 nM and induces 85% release of norepinephrine at a concentration of 10 μM.[15] For comparison, the EC50 values of methcathinone are 49.9 nM for dopamine release and 22.4 nM for norepinephrine release and it induces 100% release of norepinephrine at a concentration of 10 μM.[15][1] Hence, compared to methcathinone, 2-FMC appears to be relatively more selective or efficacious for induction of dopamine release over norepinephrine release.[15][1] In any case, the EC50 of 2-FMC for induction of norepinephrine release does not seem to be available.[15]

See also

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References

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  1. ^ a b c Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
  2. ^ Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
  3. ^ a b Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
  4. ^ Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. 87: 19–40. doi:10.1016/j.neuropharm.2014.06.012. PMID 24953830.
  5. ^ a b 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.
  6. ^ a b c d e 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.
  7. ^ a b c d Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
  8. ^ a b c d Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
  9. ^ a b c Blough BE, Landavazo A, Partilla JS, 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.
  10. ^ a b c Xue W, Fu T, Zheng G, Tu G, Zhang Y, Yang F, Tao L, Yao L, Zhu F (2020). "Recent Advances and Challenges of the Drugs Acting on Monoamine Transporters". Curr Med Chem. 27 (23): 3830–3876. doi:10.2174/0929867325666181009123218. PMID 30306851.
  11. ^ a b c Nishino S, Kotorii N (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics". Narcolepsy. Cham: Springer International Publishing. pp. 307–329. doi:10.1007/978-3-319-23739-8_22. ISBN 978-3-319-23738-1.
  12. ^ a b c 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.
  13. ^ a b Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 9: 361–90. doi:10.1007/7854_2011_125. ISBN 978-3-642-24611-1. PMID 21487953. When predicting the likely efficacy and safety of new therapeutic approaches in ADHD, the knowledge gained from existing drugs can be helpful. The pharmacological characteristics of the most effective drugs for treating ADHD, the stimulants, are summarised below and in Table 3: 1. These drugs produce large and rapid increases in the synaptic concentration of catecholamines in the PFC. 2. There is no obvious ceiling on the magnitude of their effect on catecholamine efflux. 3. The most efficacious ADHD drugs also enhance dopaminergic neurotransmission in sub-cortical brain regions. However, some caveats have to be taken into consideration. For example, lack of information in the public domain indicates that drugs that are selective dopamine releasing agents, or noradrenaline reuptake inhibitors with the pharmacological characteristics of methylphenidate, have not been evaluated as potential ADHD therapies. Hence, it is impossible to know whether sub-cortical dopamine efflux is a critical component of maximal efficacy in an ADHD medication, or alternatively, whether a drug with a selective noradrenergic mechanism that is as powerful as methylphenidate or amphetamine could rival the efficacy of the stimulants.
  14. ^ Banks ML, Bauer CT, Blough BE, 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.
  15. ^ a b c d e f Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology (Berl). 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC 6475490. PMID 30341459.
  16. ^ 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 (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.
  17. ^ Maier J, Mayer FP, Brandt SD, Sitte HH (October 2018). "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci. 9 (10): 2484–2502. doi:10.1021/acschemneuro.8b00415. PMC 6287711. PMID 30269490.
  18. ^ Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, Twamley B, Mahony O, O'Brien J, Elliott SP, Archer RP, Patrick J, Singh K, Dempster NM, Cosbey SH (2014). "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis. 6 (7–8): 684–695. doi:10.1002/dta.1668. PMC 4128571. PMID 24841869.
  19. ^ Patrick KS, Markowitz JS (November 1997). "Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder". Human Psychopharmacology: Clinical and Experimental. 12 (6): 527–546. doi:10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U. eISSN 1099-1077. ISSN 0885-6222. S2CID 144548631.
  20. ^ Nishino S, Mignot E (May 1997). "Pharmacological aspects of human and canine narcolepsy". Prog Neurobiol. 52 (1): 27–78. doi:10.1016/s0301-0082(96)00070-6. PMID 9185233. S2CID 31839355.
  21. ^ "Cylert (Pemoline)" (PDF). FDA. December 2002. Archived (PDF) from the original on 4 March 2016. Retrieved 15 February 2014.
  22. ^ J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 29–. ISBN 978-0-444-53266-4.
  23. ^ Ceci A, Garattini S, Gobbi M, Mennini T (1986). "Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain". British Journal of Pharmacology. 88 (1): 269–275. doi:10.1111/j.1476-5381.1986.tb09495.x. ISSN 0007-1188. PMC 1917102. PMID 3708219.
  24. ^ Bonnet JJ, Chagraoui A, Protais P, Costentin J (1987). "Interactions of amineptine with the neuronal dopamine uptake system: Neurochemicalin vitro and in vivo studies". Journal of Neural Transmission. 69 (3–4): 211–220. doi:10.1007/BF01244342. ISSN 0300-9564. PMID 3625193. S2CID 9886698.
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