RTI-113
Encyclopedia
RTI-113 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
." 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. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET
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
and SRI 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.
Note: Cocaine has a very strong Ki value for the 5HT3 receptor.
TMP
is a weaker dopaminergic
than 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.
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
drug which acts as a potent and fully selective dopamine reuptake inhibitor
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
(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
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
." Replacing the methyl ester in RTI-31
RTI-31
-2β-Carbomethoxy-3β-tropane 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 article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit...
with a phenyl ester makes the resultant RTI-113 fully DAT
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
specific. RTI-113 is a particularly relevant phenyltropane
Phenyltropane
Phenyltropanes 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, they are not the only researchers that have prepared these...
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
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
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
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
and SRI 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
| MAT Monoamine transporter Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters... IC50 IC50 The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half... (and Ki Dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into... ) for simple phenyltropanes with 1R,2S,3S stereochemistry Stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules.... . |
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| Compound | [3H]CFT | [3H]DA Dopaminergic Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine... |
[3H]Nisoxetine Nisoxetine Nisoxetine is a drug which inhibits the reuptake of norepinephrine . It is a racemic compound with two isomers... |
[3H]NE | [3H]Paroxetine Paroxetine Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline... |
[3H]5-HT Serotonergic Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter... |
| Cocaine Cocaine Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic... |
89.1 | 275 c.f. 241 | 3300 (1990) | 119 c.f. 161 | 1050 (45) | 177 c.f. 112 |
| WIN 35,065-2 | 23 | 49.8 | 920 (550) | 37.2 | 1960 (178) | 173 |
| WIN 35,428 | 13.9 | 23.0 | 835 (503) | 38.6 | 692 (63) | 101 |
| RTI-31 RTI-31 -2β-Carbomethoxy-3β-tropane 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 article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit... |
1.1 | 3.68 | 37 (22) | 5.86 | 44.5 (4.0) | 5.00 |
| RTI-113 RTI-113 RTI-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor . It has been suggested as a possible substitute drug for the treatment of cocaine addiction... |
1.98 | 5.25 | 2,926 | 242 | 2,340 | 391 |
| RTI-51 RTI-51 -2β-Carbomethoxy-3β-tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and... |
1.7 | ? | 37.4 (23) | ? | 10.6 (0.96) | ? |
| RTI-55 | 1.3 | 1.96 | 36 (22) | 7.51 | 4.21 (0.38) | 1.74 |
| RTI-32 RTI-32 -2β-Carbomethoxy-3β-tropane is a phenyltropane-based cocaine analog that is important in the field of medicinal chemistry for performing SAR.It has similar properties in vitro to related drugs such as RTI-31.... |
1.7 | 7.02 | 60 (36) | 8.42 | 240 (23) | 19.4 |
Note: Cocaine has a very strong Ki value for the 5HT3 receptor.
TMP
TMP
TMP can refer to any of the following:In chemistry:* Thymidine monophosphate, a nucleotide* Trimethyl phosphate, a solvent* Trimethylolpropane, a precursor to polymers* 2,2,6,6-Tetramethylpiperidine, Organic Chemistry reagent* Trimethoprim, an antibiotic...
is a weaker dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
than troparil, even though it is a more potent noradrenergic.
Interestingly, troparil is the only tropane
Tropane
Tropane is a nitrogenous bicyclic organic compound. It is mainly known for a group of alkaloids derived from it , which include, among others, atropine and cocaine. Both alkaloids contain tropinone from which tropane is a derivate...
in the above table having a [3H]NE figure that is smaller than the 3[H]DA number.