Dopamine releasing agent

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

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No selective and robust DRAs are currently known. [2] 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. [3] [4] The tryptamines, like 5-chloro-αMT, are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine. [5] 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). [6]

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). [7] [8]

Dextromethamphetamine is one of the most selective releasers of dopamine over norepinephrine, but it is still fairly balanced as an NDRA. [9] 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. [10] [11] [12] 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. [13] [14] [15]

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. [16]

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. [6]

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">Aminorex</span> Chemical compound

Aminorex is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, meaning it has high abuse potential, no accepted medical use, and a poor safety profile.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

Chlorphentermine, sold under the brand names Apsedon, Desopimon, and Lucofen, is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the para-chloro derivative of the better-known appetite suppressant phentermine, which is still in current use.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

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.

<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">4-Methylamphetamine</span> Stimulant and anorectic drug of the amphetamine class

4-Methylamphetamine is a stimulant and anorectic drug of the phenethylamine and amphetamine chemical classes.

<span class="mw-page-title-main">3-Methylamphetamine</span> Stimulant drug of the amphetamine class

3-Methylamphetamine is a stimulant drug from the amphetamine family. It is self-administered by mice to a similar extent to 4-fluoroamphetamine and has comparable properties as a monoamine releaser, although with a more balanced release of all three monoamines, as opposed to the more dopamine/noradrenaline selective fluoro analogues.

<span class="mw-page-title-main">3-Fluoroamphetamine</span> Stimulant drug that acts as an amphetamine

3-Fluoroamphetamine is a stimulant drug from the amphetamine family which acts as a monoamine releaser with similar potency to methamphetamine but more selectivity for dopamine and norepinephrine release over serotonin. It is self-administered by mice to a similar extent to related drugs such as 4-fluoroamphetamine and 3-methylamphetamine.

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">Pseudophenmetrazine</span> Chemical compound

Pseudophenmetrazine is a psychostimulant compound of the morpholine class. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine. In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug. Relative to phenmetrazine, pseudophenmetrazine is of fairly low potency, acting as a modest releasing agent of norepinephrine (EC50 = 514 nM), while its (+)-enantiomer is a weak releaser of dopamine (EC50 = 1,457 nM) whereas its (−)-enantiomer is a weak reuptake inhibitor of dopamine (Ki = 2,691 nM); together as a racemic mixture with the two enantiomers combined, pseudophenmetrazine behaves overall more as a dopamine reuptake inhibitor (Ki = 2,630 nM), possibly due to the (+)-enantiomer blocking the uptake of the (−)-enantiomer into dopaminergic neurons and thus preventing it from inducing dopamine release. Neither enantiomer has any significant effect on serotonin reuptake or release (both Ki = >10,000 nM and EC50 = >10,000 nM, respectively).

<span class="mw-page-title-main">4-Hydroxy-3-methoxymethamphetamine</span> Chemical compound

4-Hydroxy-3-methoxymethamphetamine (HMMA) is an active metabolite of 3,4-methylenedioxymethamphetamine (MDMA). It is a slightly more potent stimulant than MDMA in rodents. The drug is substantially less potent than MDMA as a monoamine releasing agent in vitro. Nonetheless, HMMA has been found to induce the release of serotonin, norepinephrine, and dopamine with EC50Tooltip half-maximal effective concentration values of 589 nM, 625 nM, and 607–2884 nM, respectively, and hence acts as a lower-potency serotonin–norepinephrine–dopamine releasing agent (SNDRA). The predicted log P of HMMA is 1.2.

References

  1. ↑ Blough B (July 2008). "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. Archived from the original on 4 November 2024.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ "Cylert (Pemoline)" (PDF). FDA. December 2002. Archived (PDF) from the original on 4 March 2016. Retrieved 15 February 2014.
  13. ↑ J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 29–. ISBN   978-0-444-53266-4.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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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