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ChEMBL | |
Chemical and physical data | |
Formula | C21H22ClNO2 |
Molar mass | 355.86 g·mol−1 |
3D model ( JSmol) | |
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(what is this?) (verify) |
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." [1] 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. [2] RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. [3] The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. [4] Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset. [4] [5]
In order for a DRI such as cocaine to induce euphoria PET scans on primates reveal that the DAT occupancy needs to be >60%. [6] 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. [3] Whereas cocaine is a fast acting rapidly metabolized DRI, RTI-113 has a longer duration span. [7]
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. [8]
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. [9]
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.
Thus, it can said with relative certainty that the DAT is responsible for the bulk of the reinforcing effects of cocaine and related stimulants. [10]
With regard to amphetamine, a recent paper disputes this claim, and makes the point that the role of NE is completely underrated. [11]
Another paper was also recently published, seeking to address the relevance of NE in cocaine pharmacology. [12]
MAT IC50 (and Ki) for simple phenyltropanes with 1R,2S,3S stereochemistry. [13] | ||||||
Compound | 3H] CFT | 3H] DA | 3H] Nisoxetine | 3H] NE | 3H] Paroxetine | 3H] 5-HT |
Cocaine [14] | 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-113 [15] | 1.98 | 5.25 | 2,926 | 242 | 2,340 | 391 |
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.
Threo-methylphenidate is a weaker dopaminergic than troparil, even though it is a more potent noradrenergic.
Troparil is the only tropane in the above table having a [3H]NE figure that is smaller than the [3H]DA number.
Identifiers | |
---|---|
| |
CAS Number |
|
PubChem CID | |
ChemSpider | |
ChEMBL | |
Chemical and physical data | |
Formula | C21H22ClNO2 |
Molar mass | 355.86 g·mol−1 |
3D model ( JSmol) | |
| |
| |
(what is this?) (verify) |
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." [1] 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. [2] RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. [3] The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. [4] Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset. [4] [5]
In order for a DRI such as cocaine to induce euphoria PET scans on primates reveal that the DAT occupancy needs to be >60%. [6] 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. [3] Whereas cocaine is a fast acting rapidly metabolized DRI, RTI-113 has a longer duration span. [7]
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. [8]
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. [9]
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.
Thus, it can said with relative certainty that the DAT is responsible for the bulk of the reinforcing effects of cocaine and related stimulants. [10]
With regard to amphetamine, a recent paper disputes this claim, and makes the point that the role of NE is completely underrated. [11]
Another paper was also recently published, seeking to address the relevance of NE in cocaine pharmacology. [12]
MAT IC50 (and Ki) for simple phenyltropanes with 1R,2S,3S stereochemistry. [13] | ||||||
Compound | 3H] CFT | 3H] DA | 3H] Nisoxetine | 3H] NE | 3H] Paroxetine | 3H] 5-HT |
Cocaine [14] | 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-113 [15] | 1.98 | 5.25 | 2,926 | 242 | 2,340 | 391 |
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.
Threo-methylphenidate is a weaker dopaminergic than troparil, even though it is a more potent noradrenergic.
Troparil is the only tropane in the above table having a [3H]NE figure that is smaller than the [3H]DA number.