|Chemical and physical data|
|Molar mass||355.85 g/mol|
|3D model (JSmol)|
RTI(-4229)-113 (2β-carbophenoxy-3β-(4-chlorophenyl)tropane) is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.
In order for a DRI such as cocaine to induce euphoria PET scans on primates reveal that the DAT occupancy needs to be >60%. Limited reinforcement may be desirable because it can help with patient compliance. DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. Whereas cocaine is a fast acting rapidly metabolized DRI, RTI-113 has a longer duration span.
Self-administration graphs are inverted U-shaped. More doses of cocaine need to be administered per session than for RTI-113 because cocaine doesn't last as long as RTI-113 does. It is easy to form the rash judgement that the NRI and SRI properties of cocaine are somehow having an additive effect on provoking self-administration of cocaine.
Although NRIs are known to inhibit DA reuptake in the prefrontal cortex where DATs are low in number, the fact that desipramine is not reliably self-administered makes it unlikely that NRIs are contributing to the addictive character of cocaine.
The 5-HT receptors are very complex to understand and can either mediate or inhibit DA release.
However, on the whole, it is understood that synaptic 5-HT counterbalances catecholamine release.
|MAT IC50 (and Ki) for simple phenyltropanes with 1R,2S,3S stereochemistry.|
|Cocaine||89.1||275 cf. 241||3300 (1990)||119 cf. 161||1050 (45)||177 cf. 112|
|Troparil||23||49.8||920 (550)||37.2||1960 (178)||173|
|WIN 35428||13.9||23.0||835 (503)||38.6||692 (63)||101|
|RTI-31||1.1||3.68||37 (22)||5.86||44.5 (4.0)||5.00|
|RTI-51||1.7||?||37.4 (23)||?||10.6 (0.96)||?|
|RTI-55||1.3||1.96||36 (22)||7.51||4.21 (0.38)||1.74|
|RTI-32||1.7||7.02||60 (36)||8.42||240 (23)||19.4|
Note: cocaine has a very strong Ki value for the 5-HT3 receptor.
Troparil is the only tropane in the above table having a [3H]NE figure that is smaller than the [3H]DA number.
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