Chemistry:RTI-113

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Short description: Chemical compound
RTI-113
Phenyltropane 24c.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC21H22ClNO2
Molar mass355.86 g·mol−1
3D model (JSmol)
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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 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.

References

  1. ↑ "Locomotor stimulant effects of novel phenyltropanes in the mouse". Drug and Alcohol Dependence 65 (1): 25–36. December 2001. doi:10.1016/S0376-8716(01)00144-2. PMID 11714587. 
  2. ↑ "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. February 2000. PMID 10640288. 
  3. ↑ 3.0 3.1 "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. January 2002. doi:10.1002/syn.10018. PMID 11746736. 
  4. ↑ 4.0 4.1 "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. September 2008. doi:10.1016/j.pbb.2008.03.032. PMID 18468667. 
  5. ↑ "A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants". Neuropsychopharmacology 31 (2): 351–362. February 2006. doi:10.1038/sj.npp.1300795. PMID 15957006. 
  6. ↑ "The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates". The Journal of Pharmacology and Experimental Therapeutics 298 (1): 1–6. July 2001. PMID 11408518. http://research.yerkes.emory.edu/Howell/JPET298.pdf. 
  7. ↑ "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. May 2002. doi:10.1016/S0014-2999(02)01501-7. PMID 12020686. 
  8. ↑ "Cocaine self-administration in dopamine-transporter knockout mice". Nature Neuroscience 1 (2): 132–137. June 1998. doi:10.1038/381. PMID 10195128. 
  9. ↑ "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. April 2005. doi:10.1038/sj.npp.1300593. PMID 15526000. 
  10. ↑ "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. June 2006. doi:10.1073/pnas.0600905103. PMID 16754872. Bibcode: 2006PNAS..103.9333C. 
  11. ↑ "Norepinephrine and stimulant addiction". Addiction Biology 14 (2): 119–129. April 2009. doi:10.1111/j.1369-1600.2008.00138.x. PMID 18811678. 
  12. ↑ "Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics 322 (2): 894–902. August 2007. doi:10.1124/jpet.107.121806. PMID 17505018. 
  13. ↑ "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. January 1995. doi:10.1021/jm00002a020. PMID 7830281. 
  14. ↑ "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. April 2003. doi:10.1124/jpet.102.046318. PMID 12649362. 
  15. ↑ "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 1229–1236. June 1999. PMID 10336510. 



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