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]
Troparil is the only tropane in the above table having a [3H]NE figure that is smaller than the [3H]DA number.
References
^Kimmel HL, Carroll FI, Kuhar MJ (December 2001). "Locomotor stimulant effects of novel phenyltropanes in the mouse". Drug and Alcohol Dependence. 65 (1): 25–36. doi:10.1016/S0376-8716(01)00144-2. PMID11714587.
^Howell LL, Czoty PW, Kuhar MJ, Carrol FI (February 2000). "Comparative behavioral pharmacology of cocaine and the selective dopamine uptake inhibitor RTI-113 in the squirrel monkey". The Journal of Pharmacology and Experimental Therapeutics. 292 (2): 521–529. PMID10640288.
^ abWilcox KM, Lindsey KP, Votaw JR, Goodman MM, Martarello L, Carroll FI, Howell LL (January 2002). "Self-administration of cocaine and the cocaine analog RTI-113: relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys". Synapse. 43 (1): 78–85. CiteSeerX10.1.1.555.2703. doi:10.1002/syn.10018. PMID11746736. S2CID26487942.
^Platt DM, Rowlett JK, Spealman RD (August 2007). "Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 322 (2): 894–902. doi:10.1124/jpet.107.121806. PMID17505018. S2CID10100028.
^Carroll FI, Kotian P, Dehghani A, Gray JL, Kuzemko MA, Parham KA, et al. (January 1995). "Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter". Journal of Medicinal Chemistry. 38 (2): 379–388. doi:10.1021/jm00002a020. PMID7830281.
^Kozikowski AP, Johnson KM, Deschaux O, Bandyopadhyay BC, Araldi GL, Carmona G, et al. (April 2003). "Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine". The Journal of Pharmacology and Experimental Therapeutics. 305 (1): 143–150. doi:10.1124/jpet.102.046318. PMID12649362. S2CID29377097.
^Damaj MI, Slemmer JE, Carroll FI, Martin BR (June 1999). "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of Pharmacology and Experimental Therapeutics. 289 (3): 1229–1236. PMID10336510.
