RTI-112 explained

RTI(-4229)-112 (2β-carbomethoxy-3β-(3-methyl-4-chlorophenyl)tropane) is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113, which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor.^[1]

In vitro tests show a very similar serotonin transporter (SERT)/dopamine transporter (DAT)/norepinephrine transporter (NET) selectivity to cocaine, although in vivo behaviour is different:

"The nonselective monoamine transporter inhibitor RTI-126 and the DAT-selective inhibitors RTI-150 and RTI-336 both had a faster rate of onset (30 min) and a short duration of action (4h). In contrast, the nonselective monoamine transporter inhibitor RTI-112 had a slower rate of onset (30–60 min) and a longer duration of action (10h). The DAT-selective inhibitors RTI-171 and RTI-177 also had slower rates of onset (30–120 min), but RTI-171 had a short duration of action (2.5 h) while RTI-177 had a very long duration of action (20 h)."

The efficacy of cocaine analogs to elicit self-administration is related to the rate at which they are administered. Slower onset analogs are less likely to function as behavioral stimulants than analogs eliciting a faster rate of onset.^[2] Nonselective analogs are less likely to function as "reinforcers" than reuptake inhibitors that have DAT specificity.^[3]

In order for a dopamine reuptake inhibitor (DRI) such as cocaine to induce euphoria, PET scans on primates reveal that the DAT occupancy needs to be >60%.^[4]

RTI-112 has equipotent in vitro affinity at the SERT, NET and DAT, respectively. RTI-112 was not reliably self-administered, in contrast to the DAT selective reuptake inhibitors that were used in this study.^[5]

In vivo at the ED50, RTI-112 had no DAT occupancy at all.^[5] At the ED50, almost all of the RTI-112 occupied the SERT at this dose.^[5] A significantly higher dose was required to get >70% DAT occupancy in the case of RTI-112;^[5] however, RTI-112 was still able to suppress cocaine administration at the ED50, suggesting a serotonergic mechanism was responsible for this.^[5]

Notes and References

1. Ginsburg BC, Kimmel HL, Carroll FI, Goodman MM, Howell LL . Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys . Pharmacology, Biochemistry, and Behavior . 80 . 3 . 481–491 . March 2005 . 15740791 . 10.1016/j.pbb.2005.01.004 . 10004289 . https://web.archive.org/web/20100611202007/http://research.yerkes.emory.edu/Howell/PB%26B80.pdf . 2010-06-11 .
2. 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 .
3. Kimmel HL, O'Connor JA, Carroll FI, Howell LL . Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys . Pharmacology, Biochemistry, and Behavior . 86 . 1 . 45–54 . January 2007 . 17258302 . 1850383 . 10.1016/j.pbb.2006.12.006 .
4. 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 . https://web.archive.org/web/20060921085211/http://research.yerkes.emory.edu/Howell/JPET298.pdf . 2006-09-21 .
5. Lindsey KP, Wilcox KM, Votaw JR, Goodman MM, Plisson C, Carroll FI, Rice KC, Howell LL . 6 . Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging . The Journal of Pharmacology and Experimental Therapeutics . 309 . 3 . 959–969 . June 2004 . 14982963 . 10.1124/jpet.103.060293 . 39794215 . 2009-07-15 . dead . https://web.archive.org/web/20100611202853/http://research.yerkes.emory.edu/Howell/JPET309.pdf . 2010-06-11 .