View source for RTI-112

{{Short description|Chemical compound}}
{{Technical|date=August 2009}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 430445180
| IUPAC_name = Methyl (1''R'',2''S'',3''S'',5''S'')-3-(4-chloro-3-methylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
| image = RTI-112.svg
<!--Clinical data-->
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| bioavailability =
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<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 143982-09-6
| CAS_number2_Ref = {{cascite|changed|??}}
| CAS_number2 = 150653-92-2
| index_label =
| index2_label = HCl
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| PubChem = 9972515
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 8148107
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1812745
<!--Chemical data-->
| C=17 | H=22 | Cl=1 | N=1 | O=2
| smiles = CC1=C(C=CC(=C1)[C@H]2C[C@@H]3CC[C@H]([C@H]2C(=O)OC)N3C)Cl
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C17H22ClNO2/c1-10-8-11(4-6-14(10)18)13-9-12-5-7-15(19(12)2)16(13)17(20)21-3/h4,6,8,12-13,15-16H,5,7,9H2,1-3H3/t12-,13+,15+,16-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = VMITZEMDDZVHBZ-XNISGKROSA-N
| melting_point =
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'''RTI(-''4229'')-112''' ('''2β-carbomethoxy-3β-(3-methyl-4-chlorophenyl)tropane''') is a synthetic [[stimulant]] drug from the [[phenyltropane]] family. In contrast to [[RTI-113]], which is DAT selective, RTI-112 is a nonselective [[triple reuptake inhibitor]].<ref name="Ginsburg_2005">{{cite journal | vauthors = Ginsburg BC, Kimmel HL, Carroll FI, Goodman MM, Howell LL | title = Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys | journal = Pharmacology, Biochemistry, and Behavior | volume = 80 | issue = 3 | pages = 481–491 | date = March 2005 | pmid = 15740791 | doi = 10.1016/j.pbb.2005.01.004 | s2cid = 10004289 | url = http://research.yerkes.emory.edu/Howell/PB&B80.pdf | archive-url = https://web.archive.org/web/20100611202007/http://research.yerkes.emory.edu/Howell/PB%26B80.pdf | archive-date = 2010-06-11 }}</ref>
''[[In vitro]]'' tests show a very similar [[serotonin transporter]] (SERT)/[[dopamine transporter]] (DAT)/[[norepinephrine transporter]] (NET) selectivity to [[cocaine]],<ref name="Lindsey_2004"/> although in vivo behaviour is different:
"The [[Serotonin–norepinephrine–dopamine reuptake inhibitor|nonselective monoamine transporter inhibitor]] [[RTI-126]] and the DAT-selective inhibitors [[RTI-150]] and [[RTI-336]] both had a faster rate of onset (30 min) and a short duration of action (4h). In contrast, the nonselective monoamine transporter inhibitor RTI-112 had a slower rate of onset (30–60 min) and a longer duration of action (10h). The DAT-selective inhibitors [[RTI-171]] and [[RTI-177]] also had slower rates of onset (30–120 min), but RTI-171 had a short duration of action (2.5 h) while [[RTI-177]] had a very long duration of action (20 h)."<ref name="Kimmel_2007"/>
The efficacy of cocaine analogs to elicit self-administration is related to the rate at which they are administered.{{clarify|date=April 2013|reason=how do cocaine analogs elicit self-administration?}} Slower onset analogs are less likely to function as behavioral stimulants than analogs eliciting a faster rate of onset.<ref>{{cite journal | vauthors = Wee S, Carroll FI, Woolverton WL | title = A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants | journal = Neuropsychopharmacology | volume = 31 | issue = 2 | pages = 351–362 | date = February 2006 | pmid = 15957006 | doi = 10.1038/sj.npp.1300795 | doi-access = free }}</ref> Nonselective analogs are less likely to function as "reinforcers" than reuptake inhibitors that have DAT specificity.<ref name="Kimmel_2007">{{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>
In order for a [[dopamine reuptake inhibitor]] (DRI) such as cocaine to induce euphoria, [[PET scan]]s on primates reveal that the DAT occupancy needs to be >60%.<ref name="Howell_2001">{{cite journal | vauthors = Howell LL, Wilcox KM | title = The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 298 | issue = 1 | pages = 1–6 | date = July 2001 | pmid = 11408518 | doi =  | url = http://research.yerkes.emory.edu/Howell/JPET298.pdf | archive-url = https://web.archive.org/web/20060921085211/http://research.yerkes.emory.edu/Howell/JPET298.pdf | archive-date = 2006-09-21 }}</ref>
RTI-112 has equipotent in vitro affinity at the SERT, NET and DAT, respectively.<ref name="Lindsey_2004"/> RTI-112 was not reliably self-administered, in contrast to the DAT selective reuptake inhibitors that were used in this study.<ref name="Lindsey_2004">{{cite journal | vauthors = Lindsey KP, Wilcox KM, Votaw JR, Goodman MM, Plisson C, Carroll FI, Rice KC, Howell LL | display-authors = 6 | title = Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 309 | issue = 3 | pages = 959–969 | date = June 2004 | pmid = 14982963 | doi = 10.1124/jpet.103.060293 | s2cid = 39794215 | url = http://research.yerkes.emory.edu/Howell/JPET309.pdf | access-date = 2009-07-15 | url-status = dead | archive-url = https://web.archive.org/web/20100611202853/http://research.yerkes.emory.edu/Howell/JPET309.pdf | archive-date = 2010-06-11 }}</ref>
In vivo at the ED50, RTI-112 had no DAT occupancy at all.<ref name="Lindsey_2004"/> At the ED50, almost all of the RTI-112 occupied the SERT at this dose.<ref name="Lindsey_2004"/> A significantly higher dose was required to get >70% DAT occupancy in the case of RTI-112;<ref name="Lindsey_2004"/> however, RTI-112 was still able to suppress cocaine administration at the ED50, suggesting a serotonergic mechanism was responsible for this.<ref name="Lindsey_2004"/>
== References ==
{{reflist|30em}}
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
{{Phenyltropanes}}
[[Category:Chlorobenzene derivatives]]
[[Category:Tropanes]]
[[Category:RTI compounds]]
[[Category:Dopamine reuptake inhibitors]]
[[Category:Stimulants]]
[[Category:Methyl esters]]