RTI-113: Difference between revisions

{{drugbox | verifiedrevid = 403041994

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

| image = RTIoneonethree.png

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| PubChem = 9886801

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

| molecular_weight = 355.85 g/mol

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

| melting_point =

| melting_high =

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'''RTI-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]]."<ref>{{Cite pmid|11714587}}</ref> Replacing the [[methyl ester]] in [[RTI-31]] with a [[phenyl]] ester makes the resultant RTI-113 fully [[Dopamine transporter|DAT]] specific. RTI-113 is a particularly relevant [[phenyltropane]] cocaine analog that has been tested on squirrel monkeys.<ref>{{Cite pmid|10640288}}</ref> RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by [[Positron emission tomography|PET]] on awake rhesus monkeys.<ref name=Wilcox>{{Cite pmid|11746736}}</ref> The efficacy of cocaine analogs to elicit self administration is closely related to the rate at which they are administered.<ref name=Kimmel/> Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.<ref name=Kimmel>{{Cite pmid|18468667}}</ref><ref>{{Cite pmid|15957006}}</ref>

In order for a DRI such as cocaine to induce euphoria PET scans on primates reveal that the DAT occupancy needs to be >60%.<ref>Howell, L.L. and Wilcox, K.M. The dopamine transporter and cocaine medication development: Drug self-administration in nonhuman primates. Journal of Pharmacology and Experimental Therapeutics, 298: 1-6, 2001. [http://research.yerkes.emory.edu/Howell/JPET298.pdf PDF]</ref> 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.<ref name=Wilcox/> Whereas cocaine is a fast acting rapidly metabolized DRI, RTI-113 has a longer duration span.<ref>{{Cite pmid|12020686}}</ref>

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 [[Norepinephrine reuptake inhibitor|NRI]] and [[Serotonin reuptake inhibitor|SRI]] properties of cocaine are somehow having an additive effect on provoking self-administration of cocaine.<ref>{{Cite pmid|10195128}}</ref>

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.<ref>{{cite journal |author=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=758–64 |year=2005 |month=April |pmid=15526000 |doi=10.1038/sj.npp.1300593}}</ref>

The 5-HT receptors are very complex to understand and can either mediate or inhibit DA 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.<ref>{{cite journal |author=Chen R, Tilley MR, Wei H, ''et al.'' |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=9333–8 |year=2006 |month=June |pmid=16754872 |pmc=1482610 |doi=10.1073/pnas.0600905103}}</ref>

With regard to amphetamine, a recent paper disputes this claim, and makes the point that the role of NE is completely underrated.<ref>{{cite journal |author=Sofuoglu M, Sewell RA |title=Norepinephrine and stimulant addiction |journal=[[Addiction Biology]] |volume=14 |issue=2 |pages=119–29 |year=2009 |month=April |pmid=18811678 |pmc=2657197 |doi=10.1111/j.1369-1600.2008.00138.x}}</ref>

Another paper was also recently published, seeking to address the relevance of NE in cocaine pharmacology.<ref>{{cite journal |author=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 |year=2007 |month=August |pmid=17505018 |doi=10.1124/jpet.107.121806}}</ref>

|colspan=7|[[Monoamine transporter|MAT]] [[IC50|IC₅₀]] (and [[Dissociation constant|K_i]]) for simple [[phenyltropanes]] with 1R,2S,3S [[stereochemistry]].<ref>{{Cite pmid|7830281}}</ref>

|Compound||[³H][[WIN 35,428|CFT]]||[³H][[Dopaminergic|DA]]||[³H][[Nisoxetine]]||[³H][[Noradrenergic|NE]]||[³H][[Paroxetine]]||[³H][[Serotonergic|5-HT]]

|[[Cocaine]]<ref>{{Cite pmid|12649362}}</ref>||89.1||<font color="red">275 [[c.f.]] 241||3300 (1990)||<font color="red">119 c.f. 161||1050 (45)||<font color="red">177 c.f. 112

|[[WIN 35,065-2]]||23||<font color="red">49.8||920 (550)||<font color="red">37.2||1960 (178)||<font color="red">173

|[[WIN 35,428]]||13.9||<font color="red">23.0||835 (503)||<font color="red">38.6||692 (63)||<font color="red">101

|[[RTI-31]]||1.1||<font color="red">3.68||37 (22)||<font color="red">5.86||44.5 (4.0)||<font color="red">5.00

|[[RTI-113]]<ref>{{Cite pmid|10336510}}</ref>||1.98||<font color="red">5.25||2,926||<font color="red">242||2,340||<font color="red">391

|[[RTI-51]]||1.7||<font color="red">?||37.4 (23)||<font color="red">?||10.6 (0.96)||<font color="red">?

|[[RTI-55]]||1.3||<font color="red">1.96||36 (22)||<font color="red">7.51||4.21 (0.38)||<font color="red">1.74

|[[RTI-32]]||1.7||<font color="red">7.02||60 (36)||<font color="red">8.42||240 (23)||<font color="red">19.4

Note: Cocaine has a very strong Ki value for the [[5HT3 receptor]].

[[TMP]] is a weaker [[dopaminergic]] than [[WIN 35,065-2|troparil]], even though it is a more potent [[noradrenergic]].

Interestingly, troparil is the only [[tropane]] in the above table having a [3H]NE figure that is smaller than the 3[H]DA number.

==References==

{{reflist|2}}

{{Phenyltropanes}}

{{Dopaminergics}}

[[Category:RTI compounds]]

[[Category:Organochlorides]]