RTI-113 explained

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. 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	[<sup>3</sup>H]CFT	[<sup>3</sup>H]DA	[<sup>3</sup>H]Nisoxetine	[<sup>3</sup>H]NE	[<sup>3</sup>H]Paroxetine	[<sup>3</sup>H]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.

Notes and References

1. Kimmel HL, Carroll FI, Kuhar MJ . Locomotor stimulant effects of novel phenyltropanes in the mouse . Drug and Alcohol Dependence . 65 . 1 . 25–36 . December 2001 . 11714587 . 10.1016/S0376-8716(01)00144-2 .
2. Howell LL, Czoty PW, Kuhar MJ, Carrol FI . 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 . 10640288 .
3. Wilcox KM, Lindsey KP, Votaw JR, Goodman MM, Martarello L, Carroll FI, Howell LL . 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 . 11746736 . 10.1002/syn.10018 . 26487942 . 10.1.1.555.2703 .
4. Kimmel HL, Negus SS, Wilcox KM, Ewing SB, Stehouwer J, Goodman MM, Votaw JR, Mello NK, Carroll FI, Howell LL . 6 . 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 . 18468667 . 2453312 . 10.1016/j.pbb.2008.03.032 .
5. Wee S, Carroll FI, Woolverton WL . 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 . 15957006 . 10.1038/sj.npp.1300795 . free .
6. Howell LL, Wilcox KM . 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 . 11408518 . dead . https://web.archive.org/web/20060921085211/http://research.yerkes.emory.edu/Howell/JPET298.pdf . 2006-09-21 .
7. Cook CD, Carroll FI, Beardsley PM . 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 . 12020686 . 10.1016/S0014-2999(02)01501-7 .
8. Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW, Caron MG . 6 . Cocaine self-administration in dopamine-transporter knockout mice . Nature Neuroscience . 1 . 2 . 132–137 . June 1998 . 10195128 . 10.1038/381 . 20444986 .
9. Gasior M, Bergman J, Kallman MJ, Paronis CA . 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 . 15526000 . 10.1038/sj.npp.1300593 . free .
10. Chen R, Tilley MR, Wei H, Zhou F, Zhou FM, Ching S, Quan N, Stephens RL, Hill ER, Nottoli T, Han DD, Gu HH . 6 . 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 . 16754872 . 1482610 . 10.1073/pnas.0600905103 . free . 2006PNAS..103.9333C .
11. Sofuoglu M, Sewell RA . Norepinephrine and stimulant addiction . Addiction Biology . 14 . 2 . 119–129 . April 2009 . 18811678 . 2657197 . 10.1111/j.1369-1600.2008.00138.x .
12. Platt DM, Rowlett JK, Spealman RD . 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 . 17505018 . 10.1124/jpet.107.121806 . 10100028 .
13. Carroll FI, Kotian P, Dehghani A, Gray JL, Kuzemko MA, Parham KA, Abraham P, Lewin AH, Boja JW, Kuhar MJ . 6 . 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 . 7830281 . 10.1021/jm00002a020 .
14. Kozikowski AP, Johnson KM, Deschaux O, Bandyopadhyay BC, Araldi GL, Carmona G, Munzar P, Smith MP, Balster RL, Beardsley PM, Tella SR . 6 . 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 . 12649362 . 10.1124/jpet.102.046318 . 29377097 .
15. Damaj MI, Slemmer JE, Carroll FI, Martin BR . Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs . The Journal of Pharmacology and Experimental Therapeutics . 289 . 3 . 1229–1236 . June 1999 . 10336510 .