RTI-336
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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.[1]
Pharmacology
It is a phenyltropane derivative that binds to the dopamine transporter with approximately 20 times the affinity of cocaine.[2] However, it produces relatively mild stimulant effects, with a slow onset and a long duration of action.[3] (Although, other sources classify it as having among the faster onsets of action among phenyltropanes.[4])
Affinity of RIT-336 and analogs for the main monoamine transporters (DAT, NET, SERT):[1]
| RTI | X | R | [3H]CFT | [3H]Nisoxetine | [3H]Paroxetine | N ÷ D | S ÷ D |
|---|---|---|---|---|---|---|---|
| Coc | — | — | 89.1 | 3298 (1986) | 1045 (45) | 37.01 | 11.79 |
| 177 | Cl | phenyl | 1.28 | 504 (304) | 2420 (220) | 393.8 | 1891 |
| 176 | Me | phenyl | 1.58 | 398 (239) | 5110 (465) | 251.9 | 3234 |
| 354 | Me | ethyl | 1.62 | 299 (180) | 6400 (582) | 184.6 | 3951 |
| 336 | Cl | p-tolyl | 4.09 | 1714 (1033) | 5741 (522) | 419.1 | 1404 |
| 386 | Me | p-anisyl | 3.93 | 756 (450) | 4027 (380) | 192.4 | 1025 |
- [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.[1][5] RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration,[4][6] and significantly reduces rates of cocaine use, especially when combined with SSRIs.[7] 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.[8]
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.[9]
Clinical studies
A dosage of up to 20mg has been tolerated in healthy males.[10]
See also
References
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