RTI-113

RTI-113
Identifiers
IUPAC name
  • Phenyl (2S,3S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC21H22ClNO2
Molar mass355.86 g·mol−1
3D model (JSmol)
SMILES
  • CN1C2CCC1[C@H]([C@H](C2)C3=CC=C(C=C3)Cl)C(=O)OC4=CC=CC=C4
InChI
  • InChI=1S/C21H22ClNO2/c1-23-16-11-12-19(23)20(21(24)25-17-5-3-2-4-6-17)18(13-16)14-7-9-15(22)10-8-14/h2-10,16,18-20H,11-13H2,1H3/t16?,18-,19?,20+/m1/s1 ☒N
  • Key:AAEKULYONKUBOZ-MLFFRYNPSA-N ☒N
 ☒NcheckY (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]89.1275 cf. 2413300 (1990)119 cf. 1611050 (45)177 cf. 112
Troparil2349.8920 (550)37.21960 (178)173
WIN 3542813.923.0835 (503)38.6692 (63)101
RTI-311.13.6837 (22)5.8644.5 (4.0)5.00
RTI-113[15]1.985.252,9262422,340391
RTI-511.7?37.4 (23)?10.6 (0.96)?
RTI-551.31.9636 (22)7.514.21 (0.38)1.74
RTI-321.77.0260 (36)8.42240 (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. ↑ 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.
  2. ↑ 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.
  3. 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. CiteSeerX 10.1.1.555.2703. doi:10.1002/syn.10018. PMID 11746736. S2CID 26487942.
  4. 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.
  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. 31 (2): 351–362. doi:10.1038/sj.npp.1300795. PMID 15957006.
  6. ↑ 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): 1–6. PMID 11408518. Archived from the original (PDF) on 2006-09-21.
  7. ↑ 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.
  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. S2CID 20444986.
  9. ↑ 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.
  10. ↑ 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. Bibcode:2006PNAS..103.9333C. doi:10.1073/pnas.0600905103. PMC 1482610. PMID 16754872.
  11. ↑ 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.
  12. ↑ 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. S2CID 10100028.
  13. ↑ 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.
  14. ↑ 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. S2CID 29377097.
  15. ↑ 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.
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