RTI(-''4229'')-112 (2β-carbomethoxy-3β-(3-methyl-4-chlorophenyl)tropane) is a synthetic

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

drug from the phenyltropane family. In contrast to RTI-113, which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor. ''

In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' tests show a very similar serotonin transporter (SERT)/

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT)/

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium ...

(NET) selectivity to

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

, although in vivo behaviour is different: "The nonselective monoamine transporter inhibitor RTI-126 and the DAT-selective inhibitors RTI-150 and RTI-336 both had a faster rate of onset (30 min) and a short duration of action (4h). In contrast, the nonselective monoamine transporter inhibitor RTI-112 had a slower rate of onset (30–60 min) and a longer duration of action (10h). The DAT-selective inhibitors RTI-171 and RTI-177 also had slower rates of onset (30–120 min), but RTI-171 had a short duration of action (2.5 h) while RTI-177 had a very long duration of action (20 h)." The efficacy of cocaine analogs to elicit self-administration is related to the rate at which they are administered. Slower onset analogs are less likely to function as behavioral stimulants than analogs eliciting a faster rate of onset. Nonselective analogs are less likely to function as "reinforcers" than reuptake inhibitors that have DAT specificity. In order for a dopamine reuptake inhibitor (DRI) such as cocaine to induce euphoria,

PET scan Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bloo ...

s on primates reveal that the DAT occupancy needs to be >60%. RTI-112 has equipotent in vitro affinity at the SERT, NET and DAT, respectively. RTI-112 was not reliably self-administered, in contrast to the DAT selective reuptake inhibitors that were used in this study. In vivo at the ED50, RTI-112 had no DAT occupancy at all. At the ED50, almost all of the RTI-112 occupied the SERT at this dose. A significantly higher dose was required to get >70% DAT occupancy in the case of RTI-112; however, RTI-112 was still able to suppress cocaine administration at the ED50, suggesting a serotonergic mechanism was responsible for this.

References

{{Phenyltropanes Chlorobenzene derivatives Tropanes RTI compounds Dopamine reuptake inhibitors Stimulants Methyl esters