RTI-113

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RTI-113
File:RTIoneonethree.png
Systematic (IUPAC) name
Phenyl 3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
Identifiers
PubChem CID 9886801
Chemical data
Formula C21H22ClNO2
Molar mass 355.85 g/mol[[Script error: No such module "String".]]
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RTI-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 c.f. 241 3300 (1990) 119 c.f. 161 1050 (45) 177 c.f. 112
WIN 35065-2 23 49.8 920 (550) 37.2 1960 (178) 173
WIN 35,428 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 5HT3 receptor.

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 3[H]DA number.

References

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  1. ↑ 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.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help) edit
  2. ↑ Howell, LL; Czoty, PW; Kuhar, MJ; Carrol, FI (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): 521–9. PMID 10640288.  edit
  3. ↑ 3.0 3.1 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 (New York, N.Y.). 43 (1): 78–85. doi:10.1002/syn.10018. PMID 11746736.  edit
  4. ↑ 4.0 4.1 Kimmel, H.; Negus, S.; Wilcox, K.; Ewing, S.; Stehouwer, J.; Goodman, M.; Votaw, J.; Mello, N.; Carroll, F. (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 Freely accessible. PMID 18468667.  edit
  5. ↑ 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 : official publication of the American College of Neuropsychopharmacology. 31 (2): 351–362. doi:10.1038/sj.npp.1300795. PMID 15957006.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help) edit
  6. ↑ Howell, L.L. and Wilcox, K.M. The dopamine transporter and cocaine medication development: Drug self-administration in nonhuman primates. Journal of Pharmacology and Experimental Therapeutics, 298: 1-6, 2001. PDF
  7. ↑ Cook, CD; Carroll, FI; Beardsley, PM (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): 93–8. doi:10.1016/S0014-2999(02)01501-7. PMID 12020686.  edit
  8. ↑ 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.  edit
  9. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  10. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  13. ↑ Carroll, FI; Kotian, P; Dehghani, A; Gray, JL; Kuzemko, MA; Parham, KA; Abraham, P; Lewin, AH; Boja, JW (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): 379–88. doi:10.1021/jm00002a020. PMID 7830281.  edit
  14. ↑ Kozikowski, P.; 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.  More than one of |first1= and |first= specified (help); More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help); More than one of |author5= and |last5= specified (help); More than one of |author6= and |last6= specified (help); More than one of |author7= and |last7= specified (help); More than one of |author8= and |last8= specified (help); More than one of |author9= and |last9= specified (help) edit
  15. ↑ Damaj, MI; Slemmer; Carroll; Martin (1999). "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of pharmacology and experimental therapeutics. 289 (3): 1229–36. PMID 10336510.  More than one of |author2= and |last2= specified (help); More than one of |author3= and |last3= specified (help); More than one of |author4= and |last4= specified (help) edit
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