RTI-336

RTI-336
Identifiers
	IUPAC name 5-[(1S,3S,4S,5R)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-4-yl]-3-(4-methylphenyl)-1,2-oxazole;
CAS Number	236754-02-2;
PubChem CID	9800708;
ChemSpider	7976471;
UNII	8QGL4KK64H;
CompTox Dashboard (EPA)	DTXSID90178343 ;
Chemical and physical data
Formula	C24H25ClN2O
Molar mass	392.93 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=CC=C(C=C1)C2=NOC(=C2)[C@@H]3[C@H]4CC[C@H](N4C)C[C@@H]3C5=CC=C(C=C5);
	InChI InChI=1S/C24H25ClN2O/c1-15-3-5-17(6-4-15)21-14-23(28-26-21)24-20(16-7-9-18(25)10-8-16)13-19-11-12-22(24)27(19)2/h3-10,14,19-20,22,24H,11-13H2,1-2H3/t19-,20+,22+,24-/m0/s1; Key:AUXUFNHAVGIVDC-IKJKNFHUSA-N;

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]

References

^ ^a ^b ^c Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (March 2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal. 8 (1): E196 – E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.
^ Carroll FI, Pawlush N, Kuhar MJ, Pollard GT, Howard JL (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. 47 (2): 296–302. doi:10.1021/jm030453p. PMID 14711303.
^ Carroll FI, Fox BS, Kuhar MJ, Howard JL, Pollard GT, Schenk S (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. 553 (1–3): 149–156. doi:10.1016/j.ejphar.2006.09.024. PMID 17067572.
^ ^a ^b Kimmel HL, O'Connor JA, Carroll FI, Howell LL (January 2007). "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. doi:10.1016/j.pbb.2006.12.006. PMC 1850383. PMID 17258302.
^ Sofuoglu M, Kosten TR (March 2006). "Emerging pharmacological strategies in the fight against cocaine addiction". Expert Opinion on Emerging Drugs. 11 (1): 91–98. doi:10.1517/14728214.11.1.91. PMID 16503828. S2CID 9675495.
^ Kimmel HL, Negus SS, Wilcox KM, Ewing SB, Stehouwer J, Goodman MM, et al. (September 2008). "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. doi:10.1016/j.pbb.2008.03.032. PMC 2453312. PMID 18468667.
^ Howell LL, Carroll FI, Votaw JR, Goodman MM, Kimmel HL (February 2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics. 320 (2): 757–765. doi:10.1124/jpet.106.108324. PMID 17105829. S2CID 9205978.
^ Czoty PW, Martelle JL, Carroll FI, Nader MA (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. 96 (3): 274–8. doi:10.1016/j.pbb.2010.05.017. PMC 2907452. PMID 20580733.
^ Andersen ML, Sawyer EK, Carroll FI, Howell LL (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. 20 (2): 77–83. doi:10.1037/a0026034. PMC 3302935. PMID 22023668.
^ Carroll FI, Kosten TR, Buda JJ, Wang L, Walters BB (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. 9: 712. doi:10.3389/fphar.2018.00712. PMC 6048956. PMID 30042675.

[Carroll_2006-1] Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (March 2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal. 8 (1): E196 – E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.

[2] Carroll FI, Pawlush N, Kuhar MJ, Pollard GT, Howard JL (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. 47 (2): 296–302. doi:10.1021/jm030453p. PMID 14711303.

[3] Carroll FI, Fox BS, Kuhar MJ, Howard JL, Pollard GT, Schenk S (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. 553 (1–3): 149–156. doi:10.1016/j.ejphar.2006.09.024. PMID 17067572.

[KimmelO'Connor2007-4] Kimmel HL, O'Connor JA, Carroll FI, Howell LL (January 2007). "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. doi:10.1016/j.pbb.2006.12.006. PMC 1850383. PMID 17258302.

[5] Sofuoglu M, Kosten TR (March 2006). "Emerging pharmacological strategies in the fight against cocaine addiction". Expert Opinion on Emerging Drugs. 11 (1): 91–98. doi:10.1517/14728214.11.1.91. PMID 16503828. S2CID 9675495.

[6] Kimmel HL, Negus SS, Wilcox KM, Ewing SB, Stehouwer J, Goodman MM, et al. (September 2008). "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. doi:10.1016/j.pbb.2008.03.032. PMC 2453312. PMID 18468667.

[7] Howell LL, Carroll FI, Votaw JR, Goodman MM, Kimmel HL (February 2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics. 320 (2): 757–765. doi:10.1124/jpet.106.108324. PMID 17105829. S2CID 9205978.

[Czoty_2010-8] Czoty PW, Martelle JL, Carroll FI, Nader MA (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. 96 (3): 274–8. doi:10.1016/j.pbb.2010.05.017. PMC 2907452. PMID 20580733.

[Andersen_2012-9] Andersen ML, Sawyer EK, Carroll FI, Howell LL (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. 20 (2): 77–83. doi:10.1037/a0026034. PMC 3302935. PMID 22023668.

[10] Carroll FI, Kosten TR, Buda JJ, Wang L, Walters BB (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. 9: 712. doi:10.3389/fphar.2018.00712. PMC 6048956. PMID 30042675.

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RTI-336

Pharmacology

Animal studies

Clinical studies

See also

References

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