Cocaine is a tropane alkaloid and central nervous system (CNS) stimulant. As an extract, it is mainly used recreationally, and often illegally for its euphoric and rewarding effects. It is also used in medicine by Indigenous South Americans for various purposes and rarely, but more formally as a local anaesthetic by medical practitioners in more developed countries. It is primarily obtained from the leaves of two Coca species native to South America; Erythroxylum coca and E. novogranatense. After extraction from the plant, and further processing into cocaine hydrochloride, the drug is administered by being either snorted, applied topically to the mouth, or dissolved and injected into a vein. It can also then be turned into free base form, in which it can be heated until sublimated and then the vapours can be inhaled.
The term narcotic originally referred medically to any psychoactive compound with numbing or paralyzing properties. In the United States, it has since become associated with opiates and opioids, commonly morphine and heroin, as well as derivatives of many of the compounds found within raw opium latex. The primary three are morphine, codeine, and thebaine.
Procaine is a local anesthetic drug of the amino ester group. It is most commonly used in dental procedures to numb the area around a tooth and is also used to reduce the pain of intramuscular injection of penicillin. Owing to the ubiquity of the trade name Novocain or Novocaine, in some regions, procaine is referred to generically as novocaine. It acts mainly as a sodium channel blocker. Today, it is used therapeutically in some countries due to its sympatholytic, anti-inflammatory, perfusion-enhancing, and mood-enhancing effects.
There are many hundreds of thousands of possible drugs. Any chemical substance with biological activity may be considered a drug. This list categorises drugs alphabetically and also by other categorisations.
Benzoylecgonine is the main metabolite of cocaine, formed by the liver and excreted in the urine. It is the compound tested for in most cocaine urine drug screens.
Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver when cocaine and ethanol coexist in the blood. In 1885, cocaethylene was first synthesized, and in 1979, cocaethylene's side effects were discovered.
(–)-2-β-Carbomethoxy-3-β-(4-fluorophenyl)tropane is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is structurally derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies. While the naphthalenedisulfonate salt is the most commonly used form in scientific research due to its high solubility in water, the free base and hydrochloride salts are known compounds and can also be produced. The tartrate is another salt form that is reported.
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, they are not the only researchers that have prepared these analogues. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.
Methylecgonidine is a chemical intermediate derived from ecgonine or cocaine.
(+)-CPCA is a stimulant drug similar in structure to pethidine and to RTI-31, but nocaine is lacking the two-carbon bridge of RTI-31's tropane skeleton. This compound was first developed as a substitute agent for cocaine.
Troparil is a stimulant drug used in scientific research. Troparil is a phenyltropane-based dopamine reuptake inhibitor (DRI) that is derived from methylecgonidine. Troparil is a few times more potent than cocaine as a dopamine reuptake inhibitor, but is less potent as a serotonin reuptake inhibitor, and has a duration spanning a few times longer, since the phenyl ring is directly connected to the tropane ring through a non-hydrolyzable carbon-carbon bond. The lack of an ester linkage removes the local anesthetic action from the drug, so troparil is a pure stimulant. This change in activity also makes troparil slightly less cardiotoxic than cocaine. The most commonly used form of troparil is the tartrate salt, but the hydrochloride and naphthalenedisulfonate salts are also available, as well as the free base.
(–)-2β-Carboisopropoxy-3β-(4-iodophenyl)tropane is a stimulant drug used in scientific research, which was developed in the early 1990s. RTI-121 is a phenyltropane based, highly selective dopamine reuptake inhibitor and is derived from methylecgonidine. RTI-121 is a potent and long-lasting stimulant, producing stimulant effects for more than 10 hours after a single dose in mice which would limit its potential uses in humans, as it might have significant abuse potential if used outside a medical setting. However RTI-121 occupies the dopamine transporter more slowly than cocaine, and so might have lower abuse potential than cocaine itself.
Dimethocaine, also known as DMC or larocaine, is a compound with a stimulatory effect. This effect resembles that of cocaine, although dimethocaine appears to be less potent. Just like cocaine, dimethocaine is addictive due to its stimulation of the reward pathway in the brain. However, dimethocaine is a legal cocaine replacement in some countries and is even listed by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) under the category “synthetic cocaine derivatives”. The structure of dimethocaine, being a 4-aminobenzoic acid ester, resembles that of procaine. It is found as a white powder at room temperature.
Dichloropane ((−)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)tropane, RTI-111, O-401) is a stimulant of the phenyltropane class that acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) with IC50 values of 3.13, 0.79 and 18 nM, respectively. In animal studies, dichloropane had a slower onset and longer duration of action compared to cocaine.
3β-(p-Fluorobenzoyloxy)tropane, (8-Methyl-8-azabicyclo[3.2.1]oct-3-yl 4-fluorobenzoic acid ester, 4-fluorotropacocaine, 3-Pseudotropyl-4-fluorobenzoate, 3-pseudotropyl-4-fluorobenzoate, pFBT) is a tropane derivative drug which acts as a local anaesthetic, having around 30% the stimulant potency of cocaine but around the same potency as a local anaesthetic. It has been investigated as a potential radiolabelled agent for studying receptor binding, but was not adopted for this application. The main application for fluorotropacocaine, however, has been as a designer drug analogue of cocaine, first detected by the EMCDDA in 2008, and subsequently sold as an ingredient of various "bath salt" powder products, usually mixed in combination with other stimulant drugs such as caffeine, dimethocaine, desoxypipradrol or substituted cathinone derivatives.
RTI(-4229)-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.
(–)-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 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.
Salicylmethylecgonine, (2′-Hydroxycocaine) is a tropane derivative drug which is both a synthetic analogue and a possible active metabolite of cocaine. Its potency in vitro is around 10x that of cocaine, although it is only around three times more potent than cocaine when administered to mice Note however that the compound 2′-Acetoxycocaine would act as a prodrug to Salicylmethylecgonine in humans, and has a more efficient partition coefficient which would act as a delivery system and would circumvent this reason for a drop in potency. Salicylmethylecgonine also shows increased behavioral stimulation compared to cocaine similar to the phenyltropanes. The hydroxy branch renders the molecule a QSAR of a 10-fold increase over cocaine in its binding potency for the dopamine transporter & a 52-fold enhanced affinity for the norepinephrine transporter. It also has a reduced selectivity for the serotonin transporter though only due to its greater increase at NET binding; its SERT affinity being 4-fold increased compared to cocaine. However, in overall binding affinity it displaces ligands better across the board than cocaine in all monoamine categories.
RTI-229, also known as (–)-3β-(4-iodophenyl)tropane-2β-pyrrolidine carboxamide and RTI-4229-229, is a potent and long-lasting stimulant drug which was developed in the 1990s as part of a large group of related analogues from the phenyltropane family. With the combination of two potent dopamine transporter (DAT) binding motifs attached to the tropane ring, the p-iodophenyl group at the 3β-position and a pyrrolidine carboxamide at 2β, RTI-229 has extremely high selectivity for the dopamine transporter and is one of the most DAT-selective compounds in the RTI series.
Cocaine reverse ester, (also known as Reverse ester cocaine or REC) is a tropane derivative drug which is a reverse ester of cocaine, with the 2-COOCH3 methoxycarbonyl group swapped to an isomeric OCOCH3 acetoxy group. It was synthesised because of the observation that the reverse ester pairs of several structurally related substances show similar activity to each other (see e.g. methylphenidate vs phacetoperane, pethidine vs desmethylprodine). Cocaine reverse ester however did not produce cocaine-like stimulant effects in animal studies, and is also illegal in many jurisdictions as a structural isomer of cocaine; nevertheless it has attracted attention from vendors of quasi-legal designer drugs as a potential alternative to cocaine.
