RTI-113
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| Identifiers | |
|---|---|
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| CAS Number |
146145-17-7  HCl: 141807-57-0 |
| PubChem (CID) | 9886801 |
| ChemSpider |
8062474 |
| ChEMBL |
CHEMBL608548 |
| Chemical and physical data | |
| Formula | C21H22ClNO2 |
| Molar mass | 355.85 g/mol |
| 3D model (Jmol) | Interactive image |
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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]
Transporter Selectivity
| 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 (TMP) is a weaker dopaminergic than troparil, even though it is a more potent noradrenergic.
Interestingly, 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; Kuhar (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. PMID 11714587.
- ↑ Howell, L. L.; Czoty, P. W.; Kuhar, M. J.; Carrol, F. I. (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. PMID 10640288.
- 1 2 Wilcox, K.; Lindsey, K.; Votaw, J.; Goodman, M.; Martarello, L.; Carroll, F.; Howell, L. (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. doi:10.1002/syn.10018. PMID 11746736.
- 1 2 Kimmel, Heather L.; Negus, S. Stevens; Wilcox, Kristin M.; Ewing, Sarah B.; Stehouwer, Jeffrey; Goodman, Mark M.; Votaw, John R.; Mello, Nancy K.; Carroll, F. Ivy; Howell, Leonard L. (2008). "Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys". Pharmacology, Biochemistry and Behavior. 90 (3): 453–462. doi:10.1016/j.pbb.2008.03.032. PMC 2453312
. PMID 18468667. - ↑ Wee, S.; Carroll, F.; Woolverton, W. (2006). "A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants". Neuropsychopharmacology. 31 (2): 351–362. doi:10.1038/sj.npp.1300795. PMID 15957006.
- ↑ Howell, L.L.; Wilcox, K.M. (2001). "The dopamine transporter and cocaine medication development: Drug self-administration in nonhuman primates" (PDF). Journal of Pharmacology and Experimental Therapeutics. 298: 1–6.
- ↑ Cook, C. D.; Carroll, F. I.; Beardsley, P. M. (2002). "RTI 113, a 3-phenyltropane analog, produces long-lasting cocaine-like discriminative stimulus effects in rats and squirrel monkeys". European Journal of Pharmacology. 442 (1–2): 93–98. doi:10.1016/S0014-2999(02)01501-7. PMID 12020686.
- ↑ Rocha, B.; Fumagalli, F.; Gainetdinov, R.; Jones, S.; Ator, R.; Giros, B.; Miller, G.; Caron, M. (1998). "Cocaine self-administration in dopamine-transporter knockout mice". Nature Neuroscience. 1 (2): 132–137. doi:10.1038/381. PMID 10195128.
- ↑ Gasior M, Bergman J, Kallman MJ, Paronis CA (April 2005). "Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys". Neuropsychopharmacology. 30 (4): 758–764. doi:10.1038/sj.npp.1300593. PMID 15526000.
- ↑ Chen R, Tilley MR, Wei H, et al. (June 2006). "Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter". Proceedings of the National Academy of Sciences of the United States of America. 103 (24): 9333–9338. doi:10.1073/pnas.0600905103. PMC 1482610. PMID 16754872.
- ↑ Sofuoglu M, Sewell RA (April 2009). "Norepinephrine and stimulant addiction". Addiction Biology. 14 (2): 119–129. doi:10.1111/j.1369-1600.2008.00138.x. PMC 2657197. PMID 18811678.
- ↑ 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. PMID 17505018.
- ↑ Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J. L.; Kuzemko, M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. (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. PMID 7830281.
- ↑ Kozikowski, A.; Johnson, K.; Deschaux, O.; Bandyopadhyay, B.; Araldi, G.; Carmona, G.; Munzar, P.; Smith, M.; Balster, R. (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. PMID 12649362.
- ↑ Damaj, M. I.; Slemmer, J. E.; Carroll, F. I.; Martin, B. R. (1999). "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of Pharmacology and Experimental Therapeutics. 289 (3): 1229–1236. PMID 10336510.