RTI-112

{{Short description|Chemical compound}}

{{Technical|date=August 2009}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 430445180

| IUPAC_name = Methyl (1R,2S,3S,5S)-3-(4-chloro-3-methylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate

| image = RTI-112.svg

| 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_Ref = {{cascite|changed|??}}

| CAS_number = 143982-09-6

| CAS_number2_Ref = {{cascite|changed|??}}

| CAS_number2 = 150653-92-2

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = TDD7WP3S39

| index_label =

| index2_label = HCl

| ATC_prefix =

| ATC_suffix =

| PubChem = 9972515

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 8148107

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1812745

| 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 =

| melting_high =

}}

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.{{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 }}

In vitro tests show a very similar serotonin transporter (SERT)/dopamine transporter (DAT)/norepinephrine transporter (NET) selectivity to cocaine, although in vivo behaviour is different:

"The 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)."

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.{{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 }} Nonselective analogs are less likely to function as "reinforcers" than reuptake inhibitors that have DAT specificity.{{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 }}

In order for a dopamine reuptake inhibitor (DRI) such as cocaine to induce euphoria, PET scans on primates reveal that the DAT occupancy needs to be >60%.{{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 = 10.1016/S0022-3565(24)29344-7| 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 }}

RTI-112 has equipotent in vitro affinity at the SERT, NET and DAT, respectively. RTI-112 was not reliably self-administered, in contrast to the DAT selective reuptake inhibitors that were used in this study.{{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 }}

In vivo at the ED50, RTI-112 had no DAT occupancy at all. At the ED50, almost all of the RTI-112 occupied the SERT at this dose. A significantly higher dose was required to get >70% DAT occupancy in the case of RTI-112; however, RTI-112 was still able to suppress cocaine administration at the ED50, suggesting a serotonergic mechanism was responsible for this.