RTI-31
Encyclopedia
-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-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 article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 x weaker than RTI-31, whereas RTI-51
was 2.6 x weaker than RTI-31.
A further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction (c.f. ritalin). This is a valid idea but the fact that these compounds have reinforcing properties which render their use addictive has served as a barrier to their introduction. RTI-31 one day might become available for use on humans, although in the mean time the related compound/s tesofensine
and brasofensine are being pursued instead.
It should be noted that RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary.
The binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT. Private discussion with F. Ivy Carroll led to confirmation that there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, because of the higher binding constant of the former compound.
Also it needs to be borne in mind the idea of transporter promiscuity. It may be possible that the NE levels are raised through DAT blockade alone (or mostly), and that little (if any) blockade of the NET is necessary to bring about this change.
RTI-31 lies somewhere in the middle of the table between troparil on one end and RTI-55 on the other. It is not as selective as RTI-113
for the DAT, but is more selective than RTI-111 is for this transporter. RTI-31 also has some muscarinic acetylcholine agonist activity.
Data in Above table from rats brains (1995). More recent work has advocated using cloned human transporter/s.
and finally desoxypipradrol
. Additionally, drugs such as sibutramine
were shown to have quite a long time of stay in the body if the dosing was daily and chronic over a period of several days/weeks.
RTI-31 is also used in the synthesis of other compounds such as RTI-113
and RTI-336.
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...
that acts as a stimulant
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...
. 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 self-administration in monkeys. WIN 35428 was 6 x weaker than RTI-31, whereas 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...
was 2.6 x weaker than RTI-31.
A further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction (c.f. ritalin). This is a valid idea but the fact that these compounds have reinforcing properties which render their use addictive has served as a barrier to their introduction. RTI-31 one day might become available for use on humans, although in the mean time the related compound/s tesofensine
Tesofensine
Tesofensine is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity...
and brasofensine are being pursued instead.
It should be noted that RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary.
Binding and Uptake Selectivity
Based on the uptake of tritiated biogenic monoamine radiotracers it can be confirmed by observing the figures in the attached table that RTI-31 is a relatively balanced reuptake inhibitor wrt the D/N/S ratio.The binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT. Private discussion with F. Ivy Carroll led to confirmation that there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, because of the higher binding constant of the former compound.
Also it needs to be borne in mind the idea of transporter promiscuity. It may be possible that the NE levels are raised through DAT blockade alone (or mostly), and that little (if any) blockade of the NET is necessary to bring about this change.
RTI-31 lies somewhere in the middle of the table between troparil on one end and RTI-55 on the other. It is not as selective as 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...
for the DAT, but is more selective than RTI-111 is for this transporter. RTI-31 also has some muscarinic acetylcholine agonist activity.
| 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 |
Data in Above table from rats brains (1995). More recent work has advocated using cloned human transporter/s.
Additional Analogs
Further chemical modification of RTI-31 leads to novel chemical entities; some of them are highly potent, and one of them has been reported as lasting for three days. This is because of the compounds impressive lipophilicity. The act of changing a drugs duration of action through altering its lipophilicity is commonly observed and not limited to this one. There are many examples of this occurring, for instance, compare Ritalin with pipradrolPipradrol
Pipradrol is a mild central nervous system stimulant that is no longer widely used in most countries due to concerns about its abuse potential, although this is less of a problem than with other stimulants that still are in current use such as methylphenidate...
and finally desoxypipradrol
Desoxypipradrol
Desoxypipradrol, also known as 2-diphenylmethylpiperidine , acts as a norepinephrine-dopamine reuptake inhibitor developed by Ciba in the 1950s...
. Additionally, drugs such as sibutramine
Sibutramine
Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...
were shown to have quite a long time of stay in the body if the dosing was daily and chronic over a period of several days/weeks.
RTI-31 is also used in the synthesis of other compounds such as 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...
and RTI-336.