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