RTI-336

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):

• [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.

References

References

1. (January 2004). "Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes". Journal of Medicinal Chemistry.
2. (December 2006). "Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration". European Journal of Pharmacology.
3. (March 2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal.
4. (March 2006). "Emerging pharmacological strategies in the fight against cocaine addiction". Expert Opinion on Emerging Drugs.
5. (September 2008). "Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys". Pharmacology, Biochemistry, and Behavior.
6. (February 2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics.
7. (September 2010). "Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates". Pharmacology, Biochemistry, and Behavior.
8. (April 2012). "Influence of chronic dopamine transporter inhibition by RTI-336 on motor behavior, sleep, and hormone levels in rhesus monkeys". Experimental and Clinical Psychopharmacology.
9. (10 July 2018). "A Double-Blind, Placebo-Controlled Trial Demonstrating the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of RTI-336". Frontiers in Pharmacology.