View source for 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=
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| CAS_number = 236754-02-2
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| PubChem = 9800708
| ChEMBL_Ref = {{ebicite|correct|EBI}}
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| UNII = 8QGL4KK64H
| ChemSpiderID = 7976471
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| 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
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'''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]],<ref>{{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 }}</ref> however it produces relatively mild stimulant effects, with a slow onset and long duration of action.<ref>{{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 }}</ref> (however other sources class it as having among the faster onsets of action from among phenyltropanes<ref name="KimmelO'Connor2007">{{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 }}</ref>) These characteristics make it a potential candidate for treatment of cocaine [[Substance dependence|addiction]], as a possible substitute drug analogous to how [[methadone]] is used for treating [[heroin]] abuse.<ref>{{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 }}</ref><ref>{{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 }}</ref> RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration,<ref>{{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 }}</ref><ref>{{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 }}</ref> and significantly reduces rates of cocaine use, especially when combined with [[SSRI]]s,<ref>{{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 }}</ref> and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.
==Update==
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907452/?tool=pubmed Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates.]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302935/?tool=pubmed Influence of chronic dopamine transporter inhibition by RTI-336 on motor behavior, sleep and hormone levels in rhesus monkeys.]
==Pharmacotherapy for Cocaine Abuse==
[http://www.aapsj.org/view.asp?art=aapsj080124 Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse (FIC, et al. 2006).]
[[File:LMAgraph.GIF|left]]
[[File:RTI336.png|200px|left]]
[[File:HeteroCD.GIF]]
{| class="wikitable" style="margin:auto"
|-
! RTI!!X!!R!![<sup>3</sup>H]CFT!![<sup>3</sup>H]Nisoxetine!![<sup>3</sup>H]Paroxetine!!N ÷ D!!S ÷ D
|- align="center"
| Coc||—||—||89.1||3298 (1986)||1045 (45)||37.01||11.79
|- align="center"
| 177||Cl||phenyl||1.28||504 (304)||2420 (220)||393.8||1891
|- align="center"
| 176||Me||phenyl||1.58||398 (239)||5110 (465)||251.9||3234
|- align="center"
| 354||Me||ethyl||1.62||299 (180)||6400 (582)||184.6||3951
|- align="center"
| 336||Cl||''p''-tolyl||4.09||1714 (1033)||5741 (522)||419.1||1404
|- align="center"
| 386||Me||''p''-anisyl||3.93||756 (450)||4027 (380)||192.4||1025
|}
N.B. [[RTI-371]]<ref>{{cite journal | vauthors = Navarro HA, Howard JL, Pollard GT, Carroll FI | title = Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter | journal = British Journal of Pharmacology | volume = 156 | issue = 7 | pages = 1178–84 | date = April 2009 | pmid = 19226282 | pmc = 2697692 | doi = 10.1111/j.1476-5381.2009.00124.x }}</ref>
== See also ==
* [[RTI-177]]
* [[List of cocaine analogues]]
== References ==
{{reflist|32em}}
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
{{Phenyltropanes}}
[[Category:4-Chlorophenyl compounds]]
[[Category:Tropanes]]
[[Category:RTI compounds]]
[[Category:Dopamine reuptake inhibitors]]
[[Category:Stimulants]]
[[Category:Isoxazoles]]
[[Category:4-Tolyl compounds]]