RTI-336

{{Short description|Chemical compound}}

{{Drugbox

| 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

| image= RTI-336 Structure.svg

| width=

| tradename =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US =

| legal_status =

| routes_of_administration =

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number = 236754-02-2

| ATC_prefix =

| ATC_suffix =

| PubChem = 9800708

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL =

| UNII = 8QGL4KK64H

| ChemSpiderID = 7976471

| C=24 | H=25 | Cl=1 | N=2 | O=1

| 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)

| StdInChI = 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

| StdInChIKey = AUXUFNHAVGIVDC-IKJKNFHUSA-N

| melting_point =

| melting_high =

}}

RTI(-4229)-336, (LS-193,309, (−)-2β-(3-(4-methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane) is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine,{{cite journal | vauthors = Carroll FI, Pawlush N, Kuhar MJ, Pollard GT, Howard JL | title = Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 2 | pages = 296–302 | date = January 2004 | pmid = 14711303 | doi = 10.1021/jm030453p }} however it produces relatively mild stimulant effects, with a slow onset and long duration of action.{{cite journal | vauthors = Carroll FI, Fox BS, Kuhar MJ, Howard JL, Pollard GT, Schenk S | title = Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration | journal = European Journal of Pharmacology | volume = 553 | issue = 1–3 | pages = 149–56 | date = December 2006 | pmid = 17067572 | doi = 10.1016/j.ejphar.2006.09.024 }} (however other sources class it as having among the faster onsets of action from among phenyltropanes{{cite journal | vauthors = Kimmel HL, O'Connor JA, Carroll FI, Howell LL | title = Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys | journal = Pharmacology, Biochemistry, and Behavior | volume = 86 | issue = 1 | pages = 45–54 | date = January 2007 | pmid = 17258302 | pmc = 1850383 | doi = 10.1016/j.pbb.2006.12.006 }}) These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse.{{cite journal | vauthors = Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ | title = Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse | journal = The AAPS Journal | volume = 8 | issue = 1 | pages = E196-203 | date = March 2006 | pmid = 16584128 | pmc = 2751440 | doi = 10.1208/aapsj080124 }}{{cite journal | vauthors = Sofuoglu M, Kosten TR | title = Emerging pharmacological strategies in the fight against cocaine addiction | journal = Expert Opinion on Emerging Drugs | volume = 11 | issue = 1 | pages = 91–8 | date = March 2006 | pmid = 16503828 | doi = 10.1517/14728214.11.1.91 | s2cid = 9675495 }} RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration,{{cite journal | vauthors = Kimmel HL, Negus SS, Wilcox KM, Ewing SB, Stehouwer J, Goodman MM, Votaw JR, Mello NK, Carroll FI, Howell LL | display-authors = 6 | title = Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys | journal = Pharmacology, Biochemistry, and Behavior | volume = 90 | issue = 3 | pages = 453–62 | date = September 2008 | pmid = 18468667 | pmc = 2453312 | doi = 10.1016/j.pbb.2008.03.032 }} and significantly reduces rates of cocaine use, especially when combined with SSRIs,{{cite journal | vauthors = Howell LL, Carroll FI, Votaw JR, Goodman MM, Kimmel HL | title = Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 2 | pages = 757–65 | date = February 2007 | pmid = 17105829 | doi = 10.1124/jpet.106.108324 | s2cid = 9205978 }} and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.

A dosage of up to 20mg has been tolerated in healthy males.{{cite journal | vauthors=((Carroll, F. I.)), ((Kosten, T. R.)), ((Buda, J. J.)), ((Wang, L.)), ((Walters, B. B.)) | journal=Frontiers in Pharmacology | title=A Double-Blind, Placebo-Controlled Trial Demonstrating the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of RTI-336 | volume=9 | pages=712 | date=10 July 2018 | issn=1663-9812 | doi=10.3389/fphar.2018.00712| doi-access=free | pmid=30042675 | pmc=6048956 }}