RTI-113

{{Short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 424736268

| IUPAC_name = Phenyl (2S,3S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate

| image = Phenyltropane 24c.svg

| tradename =

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| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 146145-17-7

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

| UNII = G6867RWN6N

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

| CAS_number2 = 141807-57-0

| index_label =

| index2_label = HCl

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| PubChem = 9886801

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

| ChemSpiderID = 8062474

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

| ChEMBL = 608548

| C=21 | H=22 | Cl=1 | N=1 | O=2

| smiles = CN1C2CCC1[C@H]([C@H](C2)C3=CC=C(C=C3)Cl)C(=O)OC4=CC=CC=C4

| melting_point =

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| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C21H22ClNO2/c1-23-16-11-12-19(23)20(21(24)25-17-5-3-2-4-6-17)18(13-16)14-7-9-15(22)10-8-14/h2-10,16,18-20H,11-13H2,1H3/t16?,18-,19?,20+/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = AAEKULYONKUBOZ-MLFFRYNPSA-N

}}

RTI(-4229)-113 (2β-carbophenoxy-3β-(4-chlorophenyl)tropane) is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine."{{cite journal | vauthors = Kimmel HL, Carroll FI, Kuhar MJ | title = Locomotor stimulant effects of novel phenyltropanes in the mouse | journal = Drug and Alcohol Dependence | volume = 65 | issue = 1 | pages = 25–36 | date = December 2001 | pmid = 11714587 | doi = 10.1016/S0376-8716(01)00144-2 }} Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys.{{cite journal | vauthors = Howell LL, Czoty PW, Kuhar MJ, Carrol FI | title = Comparative behavioral pharmacology of cocaine and the selective dopamine uptake inhibitor RTI-113 in the squirrel monkey | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 292 | issue = 2 | pages = 521–529 | date = February 2000 | doi = 10.1016/S0022-3565(24)35321-2 | pmid = 10640288 }} RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys.{{cite journal | vauthors = Wilcox KM, Lindsey KP, Votaw JR, Goodman MM, Martarello L, Carroll FI, Howell LL | title = Self-administration of cocaine and the cocaine analog RTI-113: relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys | journal = Synapse | volume = 43 | issue = 1 | pages = 78–85 | date = January 2002 | pmid = 11746736 | doi = 10.1002/syn.10018 | s2cid = 26487942 | citeseerx = 10.1.1.555.2703 }} The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.{{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 = 453–462 | date = September 2008 | pmid = 18468667 | pmc = 2453312 | doi = 10.1016/j.pbb.2008.03.032 }}{{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 }}

In order for a 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 | doi = 10.1016/S0022-3565(24)29344-7 | pmid = 11408518 | url = http://research.yerkes.emory.edu/Howell/JPET298.pdf | url-status = dead | archive-url = https://web.archive.org/web/20060921085211/http://research.yerkes.emory.edu/Howell/JPET298.pdf | archive-date = 2006-09-21 }} Limited reinforcement may be desirable because it can help with patient compliance. DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. Whereas cocaine is a fast acting rapidly metabolized DRI, RTI-113 has a longer duration span.{{cite journal | vauthors = Cook CD, Carroll FI, Beardsley PM | title = RTI 113, a 3-phenyltropane analog, produces long-lasting cocaine-like discriminative stimulus effects in rats and squirrel monkeys | journal = European Journal of Pharmacology | volume = 442 | issue = 1–2 | pages = 93–98 | date = May 2002 | pmid = 12020686 | doi = 10.1016/S0014-2999(02)01501-7 }}

Self-administration graphs are inverted U-shaped. More doses of cocaine need to be administered per session than for RTI-113 because cocaine doesn't last as long as RTI-113 does. It is easy to form the rash judgement that the NRI and SRI properties of cocaine are somehow having an additive effect on provoking self-administration of cocaine.{{cite journal | vauthors = Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW, Caron MG | display-authors = 6 | title = Cocaine self-administration in dopamine-transporter knockout mice | journal = Nature Neuroscience | volume = 1 | issue = 2 | pages = 132–137 | date = June 1998 | pmid = 10195128 | doi = 10.1038/381 | s2cid = 20444986 }}

Although NRIs are known to inhibit DA reuptake in the prefrontal cortex where DATs are low in number, the fact that desipramine is not reliably self-administered makes it unlikely that NRIs are contributing to the addictive character of cocaine.{{cite journal | vauthors = Gasior M, Bergman J, Kallman MJ, Paronis CA | title = Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys | journal = Neuropsychopharmacology | volume = 30 | issue = 4 | pages = 758–764 | date = April 2005 | pmid = 15526000 | doi = 10.1038/sj.npp.1300593 | doi-access = free }}

The 5-HT receptors are very complex to understand and can either mediate or inhibit DA release.

However, on the whole, it is understood that synaptic 5-HT counterbalances catecholamine release.

Thus, it can said with relative certainty that the DAT is responsible for the bulk of the reinforcing effects of cocaine and related stimulants.{{cite journal | vauthors = Chen R, Tilley MR, Wei H, Zhou F, Zhou FM, Ching S, Quan N, Stephens RL, Hill ER, Nottoli T, Han DD, Gu HH | display-authors = 6 | title = Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 24 | pages = 9333–9338 | date = June 2006 | pmid = 16754872 | pmc = 1482610 | doi = 10.1073/pnas.0600905103 | doi-access = free | bibcode = 2006PNAS..103.9333C }}

With regard to amphetamine, a recent paper disputes this claim, and makes the point that the role of NE is completely underrated.{{cite journal | vauthors = Sofuoglu M, Sewell RA | title = Norepinephrine and stimulant addiction | journal = Addiction Biology | volume = 14 | issue = 2 | pages = 119–129 | date = April 2009 | pmid = 18811678 | pmc = 2657197 | doi = 10.1111/j.1369-1600.2008.00138.x }}

Another paper was also recently published, seeking to address the relevance of NE in cocaine pharmacology.{{cite journal | vauthors = Platt DM, Rowlett JK, Spealman RD | title = Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 2 | pages = 894–902 | date = August 2007 | pmid = 17505018 | doi = 10.1124/jpet.107.121806 | s2cid = 10100028 }}