RTI(-''4229'')-113 (2β-carbophenoxy-3β-(4-chlorophenyl)tropane) is a stimulant drug which acts as a potent and fully selective

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

(DRI). It has been suggested as a possible substitute drug for the treatment of

cocaine addiction Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use of coc ...

. "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 Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

." Replacing the

methyl ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

RTI-31 (–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-''4229''-31) is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the ar ...

with a

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant

phenyltropane Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, ...

cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by

PET A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive appearances, intelligence ...

on awake rhesus monkeys. 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. In order for a DRI such as cocaine to induce euphoria PET scans on primates reveal that the DAT occupancy needs to be >60%. 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. 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 NRI or Nri may refer to : * Kingdom of Nri, an Igbo kingdom that flourished between the 10th century and early 20th century * National Radio Institute, a now defunct post-secondary vocational correspondence school * National Resources Inventory * N ...

and

SRI Shri (; , ) is a Sanskrit term denoting resplendence, wealth and prosperity, primarily used as an honorific. The word is widely used in South and Southeast Asian languages such as Marathi, Malay (including Indonesian and Malaysian), Javanes ...

properties of cocaine are somehow having an additive effect on provoking self-administration of cocaine. 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. 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. With regard to amphetamine, a recent paper disputes this claim, and makes the point that the role of NE is completely underrated. Another paper was also recently published, seeking to address the relevance of NE in cocaine pharmacology.

Transporter Selectivity

Note: cocaine has a very strong Ki value for the 5-HT₃ receptor. Threo-methylphenidate is a weaker dopaminergic than

troparil Troparil (also known as (–)-2β-Carbomethoxy-3β-phenyltropane, WIN 35,065-2, or β-CPT) is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine ...

, even though it is a more potent

noradrenergic Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

. Troparil is the only

tropane Tropane is a nitrogenous bicyclic organic compound. It is mainly known for the other alkaloids derived from it, which include atropine and cocaine, among others. Tropane alkaloids occur in plants of the families Erythroxylaceae (including coca) ...

in the above table having a sup>3HE figure that is smaller than the sup>3HA number.

References

{{Phenyltropanes Tropanes RTI compounds Dopamine reuptake inhibitors Stimulants Chlorobenzenes