A serotonin-dopamine reuptake inhibitor (SDRI ) is a type of drug that acts as a serotonin reuptake neurotransmitter monoamine and dopamine by blocking the action of the serotonin transporter (SERT) and dopamine transporter (DAT) , each. This in turn leads to an increase in extracellular concentrations of serotonin and dopamine, and therefore, an increase in serotonergic and dopaminergic neurotransmissions.
The type of drug that is closely related is a serotonin-dopamine release agent (SDRA).
Video Serotonin-dopamine reuptake inhibitor
Comparison with SNDRIs
Relative to serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), which also inhibit norepinephrine reuptake in addition to serotonin and dopamine, SDRI may be expected to have a decrease in the incidence of certain side effects, insomnia, loss of appetite, anxiety, and heart rate and blood pressure change.
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Sample SDRI
Unlike the case of the combination of other monoamine reuptake inhibitors such as serotonin-norepinephrine reuptake (SNRI) inhibitors and norepinephrine-dopamine (NDRI) reuptake inhibitors, because the chemical structure of the substrate is very similar, it is very difficult to separate the affinity for DAT from norepinephrine (NET) transporters and inhibit reuptake dopamine alone. As a result, selective dopamine reuptake inhibitors (DRIs) are rare, and comparable, even more SDRIs.
Pharmaceutical drugs
Medifoxamine (Cledial, Gerdaxyl) is an antidepressant that seems to act as an SDRI as well as a 5-HT receptor antagonist 2 . Sibutramine (Reductil, Meridia, Siredia, Sibutrex) is anorectically withdrawn as an in vitro molecule is a SNDRI but is preferably an SDRI, with an 18.3- and 5.8-fold preference to inhibit serotonin reuptake and dopamine over norepinephrine , each. However, sibutramine metabolites are substantially more powerful and have different ratios of monoamine reuptake inhibition in comparison, and sibutramine seems to act in vivo primarily as a prodrug to them; accordingly, it was found to act as a SNRI (73% and 54% for inhibition of norepinephrine and serotonin reuptake, respectively) in human volunteers with only very weak inhibition of dopamine reuptake (16%).
Sertraline
Sertraline (Zoloft) is a selective serotonin reuptake inhibitor (SSRI), but, uniquely among most antidepressants, it exhibits a relatively high affinity (nanomolar) for DAT as well. Thus, it has been suggested that it may clinically inhibit reuptake of dopamine, especially at high doses. For this reason, sertraline is sometimes described as SDRI. This is relevant because dopamine is thought to be involved in the pathophysiology of depression, and an increase in dopaminergic signals by sertraline in addition to serotonin may have an added benefit to depression.
Tatsumi et al. (1997) found the value of K i of sertraline in SERT, DAT and NET respectively 0.29, 25, and 420Ã, nM. Sertraline selectivity for SERT over DAT is 86-fold. In many cases, of the various antidepressants assessed in this study, sertraline showed the highest affinity of all for DAT, even higher than the norepinephrine-dopamine reuptake inhibitor (NDRI) numeral (K i = 56Ã, nM ) and bupropion (K i = 520Ã, nM). Sertraline is also said to have similarities to DAT as a methylphenidate NDRI. It should be noted that tametraline (CP-24,441), a very close sertraline analogue and a sertraline origin compound, is a non-marketed NDRI.
A single dose of 50 to 200 mg of sertraline has been found to produce a peak plasma concentration of 20 to 55 ng/mL (65-180 m), while chronic treatment with 200 mg/day of sertraline, the recommended maximum dose, has been found to produce maximal plasma levels of 118 to 166 ng/mL (385-542 m). However, sertraline is highly protein bound in plasma, with a 98.5% bound fraction. Therefore, only 1.5% are free and theoretically bioactive. Based on this percentage, the free sertraline concentration would be 2.49 ng/mL (8.13 mM) at most, which is only about one-third of the K i value of Tatsumi et al. found with sertraline in DAT. A very high dose of sertraline of 400 mg/day has been found to produce a peak plasma concentration of about 250 ng/mL (816 nM). This can be estimated to yield a free concentration of 3.75 ng/mL (12.2 m), which is still only about half of K i of sertraline for DAT.
Thus, it seems unlikely that sertraline will produce much inhibition of dopamine reuptake even at clinically used doses well beyond the maximum recommended clinical dose. This corresponds to an 86-fold selectivity for SERT over DAT and hence the fact that nearly 100 times higher levels of sertraline would be needed to also inhibit reuptake of dopamine. Appropriate, while sertraline has a very low abuse potential and may even dislike clinical doses, sertraline abuse case reports describe effects such as dopaminergic such as euphoria, mental overactivity, and hallucinations only at doses of 56 times the normal maximum and 224 times the normal minimum. For this reason, the significant inhibition of dopamine reuptake by sertraline in controversial clinical doses, and the work by sertraline from DAT is considered by many clinically irrelevant experts.
Research chemicals
Two SDRIs known in the current study are RTI-83 and UWA-101, although other related compounds are also known. Based on its chemical structure, UWA-101 may actually also have some activity as a release agent, and if so, unlike RTI-83, it would not be SDRI in its purest sense and would also be the SDRA. Manning et al. presents two high affinity ligaments with good binding selectivity for SERT and DAT, ie 4-indolyl and 1-naphthyl arylalkylamines ent -16b (K i 0.82, 3.8, 4840 nM for SERT, DAT, NET) and ent -13b respectively. AN-788 (NSD-788) is another SDRI, and has been developed for the treatment of depression and anxiety disorders.
See also
- Monoamine reuptake inhibitor
- Dopamine reuptake inhibitor
- Serotonin reuptake inhibitor
References
External links
- Media associated with Serotonin-dopamine reuptake inhibitors on Wikimedia Commons
Source of the article : Wikipedia
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