RTI-336, also known as RTI-4229-336 or LS-193,309 is a potent and selective dopamine reuptake inhibitor that was initially developed by the Research Triangle Institute, now known as RTI International.
Pharmacology
It is a phenyltropane derivative that binds to the dopamine transporter with approximately 20 times the affinity of cocaine. However, it produces relatively mild stimulant effects, with a slow onset and a long duration of action. (Although, other sources classify it as having among the faster onsets of action among phenyltropanes.)
Affinity of RIT-336 and analogs for the main monoamine transporters (DAT, NET, SERT):
RTIXR[3H]CFT[3H]Nisoxetine[3H]ParoxetineN ÷ DS ÷ D Coc——89.13298 (1986)1045 (45)37.0111.79 177Clphenyl1.28504 (304)2420 (220)393.81891 176Mephenyl1.58398 (239)5110 (465)251.93234 354Meethyl1.62299 (180)6400 (582)184.63951 336Clp-tolyl4.091714 (1033)5741 (522)419.11404 386Mep-anisyl3.93756 (450)4027 (380)192.41025
[3H]CFT: [3H]CFT is a selective radioligand for the dopamine transporter (DAT) [3H]Nisoxetine: This is a radioligand for the norepinephrine transporter (NET) [3H]Paroxetine: This is a radioligand for the serotonin transporter (SERT) N ÷ D: ratio of norepinephrine transporter (NET) affinity to dopamine transporter (DAT) affinity S ÷ D: ratio of serotonin transporter (SERT) affinity to dopamine transporter (DAT) affinity
Animal studies
These characteristics make it a potential candidate for the treatment of cocaine addiction, as a possible substitute drug, analogous to the use of methadone for treating heroin dependence. RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration, and significantly reduces rates of cocaine use, especially when combined with SSRIs. Research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.
RTI-336 and RTI-177 exhibited lower reinforcing strength than cocaine in nonhuman primates, indicating reduced abuse liability and supporting their viability as pharmacotherapies for addiction.
Chronic RTI-336 administration in rhesus monkeys altered motor activity and sleep patterns but did not cause adverse hormonal changes, suggesting a relatively safe profile for long-term therapeutic use.
Clinical studies
A dosage of up to 20mg has been tolerated in healthy males.
See also RTI-177 List of cocaine analogues
References