SoRI-20041 is an " antagonist-like"

allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

-induced

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...

release (in contrast to the related research chemicals SoRI-9804 and SoRI-20040, which are "

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

-like"). SoRI-20041 is believed to be the first example of a drug that separately modulates uptake versus release in the

dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...

(possibly showing how inward and outward transport represent distinct operational modes of DAT); it produces the same effects as SoRI-20040 and SoRI-9804 in uptake assays and binding assays, inhibiting the re-uptake of dopamine, but does not modulate d-amphetamine- induced DA release by inhibiting that as well, like 'agonists' of the series do. This suggests the possibility of simultaneous action and increase of indirect-agonism through the dual action of DRA and DRI efficacy existing together. This increases the inhibition of re-uptake at synaptic dopamine concentrations without interfering in the flow of release of dopamine from amphetaminergic phosphorylation at the affected transporter. This overcomes the obstacle of a compromised binding site that would be rendered unusable through the action of amphetamine. Conventional dopamine re-uptake inhibitors (such as

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...

) would otherwise ineffectively target such a site on each specific transporter so affected by amphetamine, making this an example of a DRI that does not have a mutually exclusive functionality against DRA action at individual instances of DAT.

References

{{Dopaminergics Neurochemistry