Dopamine releasing agent

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known.^[1] On the other hand, many 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. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed.^[2]^[3] Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).^[4]

A closely related type of drug is a dopamine reuptake inhibitor (DRI). Various selective DRIs are known, like amineptine, modafinil, and vanoxerine, in contrast to the case of DRAs. It is of particular note that the mechanism of action at the dopamine transporter (DAT) for dopamine releasers/substrates is entropy-driven (i.e. hydrophobic), whereas for dopamine re-uptake inhibitors it is enthalpy-driven (i.e. conformational change).^[5]^[6]

Dextromethamphetamine is one of the most selective releasers of dopamine over norepinephrine, but it is still fairly balanced as an NDRA.^[7] Another of the most specific dopamine releasers is recreational stimulant 4-methylaminorex, but it also has considerable activity as a norepinephrine releaser and hence is likewise not a selective DRA.^{[citation needed]} Pemoline, which is structurally related to the aminorex drugs, is a stimulant used to treat ADHD which acts as a selective DRI and DRA, but only weakly stimulates dopamine release.^[8]^[9]^[10] There is 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 that of norepinephrine or serotonin.^[11]^[12]^[13]

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.^[14]

Selective DRAs might have different clinical effects in the treatment of attention deficit hyperactivity disorder (ADHD) than the NDRAs like amphetamines that are currently used.^[4]

References

^ 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): 627–36. 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.
^ Blough BE, Landavazo A, Partilla JS, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–8. doi:10.1016/j.bmcl.2014.07.062. PMC 4211607. PMID 25193229.
^ 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): 274–84. doi:10.1037/a0036595. PMC 4067459. PMID 24796848.
^ ^a ^b Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics". Curr Top Behav Neurosci. 9: 361–90. doi:10.1007/7854_2011_125. 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.
^ Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000 ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Page 928 (4th of article) 1st paragraph. Lines 8—11. Mirror hotlink.
^ Bonnet JJ, Benmansour S, Costentin J, Parker EM, Cubeddu LX (June 1990). "Thermodynamic analyses of the binding of substrates and uptake inhibitors on the neuronal carrier of dopamine labeled with [3H]GBR 12783 or [3H]mazindol". The Journal of Pharmacology and Experimental Therapeutics. 253 (3): 1206–14. PMID 2141637.
^ Rothman RB, Baumann MH (2003). "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
^ 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.
^ 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.
^ "Cylert (Pemoline)" (PDF). FDA. December 2002. Archived (PDF) from the original on 4 March 2016. Retrieved 15 February 2014.
^ J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 29–. ISBN 978-0-444-53266-4.
^ 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.
^ 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.
^ 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.

External links

Media related to Dopamine releasing agents at Wikimedia Commons

[pmid17071819-1] 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): 627–36. 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.

[pmid25193229-2] Blough BE, Landavazo A, Partilla JS, et al. (October 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. 24 (19): 4754–8. doi:10.1016/j.bmcl.2014.07.062. PMC 4211607. PMID 25193229.

[pmid24796848-3] 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): 274–84. doi:10.1037/a0036595. PMC 4067459. PMID 24796848.

[HealSmithFindling2012-4] Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics". Curr Top Behav Neurosci. 9: 361–90. doi:10.1007/7854_2011_125. 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.

[5] Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000 ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Page 928 (4th of article) 1st paragraph. Lines 8—11. Mirror hotlink.

[pmid2141637-6] Bonnet JJ, Benmansour S, Costentin J, Parker EM, Cubeddu LX (June 1990). "Thermodynamic analyses of the binding of substrates and uptake inhibitors on the neuronal carrier of dopamine labeled with [3H]GBR 12783 or [3H]mazindol". The Journal of Pharmacology and Experimental Therapeutics. 253 (3): 1206–14. PMID 2141637.

[pmid14612135-7] Rothman RB, Baumann MH (2003). "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.

[PatrickMarkowitz1997-8] 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.

[NishinoMignot1997-9] 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.

[Cylert-Label-10] "Cylert (Pemoline)" (PDF). FDA. December 2002. Archived (PDF) from the original on 4 March 2016. Retrieved 15 February 2014.

[Aronson2009-11] J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 29–. ISBN 978-0-444-53266-4.

[CeciGarattini1986-12] 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.

[BonnetChagraoui1987-13] 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.

[RothmanBloughBaumann2007-14] 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.

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Dopamine releasing agent

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