Derivation, of cocaine

While cocaine is still used for ear, nose, and throat surgery, Lidocaine, a synthetic derivative of cocaine, is the most widely used local anesthetic. 

From the time when Koller (1) in 1884 demonstrated that cocaine could be used successfully in eye surgery, the search for compounds that produce loss of pain sensation has been promoted in the fields of both natural and synthetic products. It was to be expected that much of the early work would be concerned with modifications and derivatives of cocaine, and the search for other alkaloids possessing similar properties. 

Cocaine Cocaine, the most powerful natural stimulant, is widely abused and very dangerous. A powerful derivative of cocaine called crack (or rock), is also used, and is known as one of the most powerfully addictive drugs on the illegal market. 

The liabitat of Erythroxylon spp. is principally the western side of Soutl America, and although indigenous species occur in India, Africa anc Australia, they have no economic value. Two kinds of coca leaves ar< available in commerce, Bolivian or Huanuco leaves derived from E. coce Lam. and Peruvian or Truxillo leaves obtained from E. truxillense Rusby both are cultivated in Java. In South America coca leaves are chewee with lime by the Indians as a stimulant, and are exported to Europe foi use in medicine and for the preparation of cocaine, but the prineipal sourc< of coca leaves is Java. Crude cocaine is manufactured in South Americi and exported for refining and some aspects of this industry have beei discussed recently. ... 

Accepting this view of the constitution of ecgonine, the formulae of its derivatives and of cocaine may be written as follows anhydroecgoninc (VII), ecgonine (VIII), norecgonine (IX) and cocaine (X). 

Trachelantamine, according to Syrneva, has a weak atropine-like action and also produces local anaesthesia. Its hydrolytic product, trache-lantamidine, which is structurally identical with tsoretronecanol, yields a p-aminobenzoyl derivative of -which the crystalline hydrochloride, m.p. 230-2°, is said to be as potent a local anaesthetic as cocaine hydrochloride. The chloro- -heliotridane (p. 606) formed by the aetion of thionyl ehloride on trachelantamidine reacts with 6-methoxy-8-aminoquinoline to form 6-methoxy-8-(pseMdoheliotridylamino)-quinoline,... 

Heikkila, R.E., Manzino, L., and Cabbat, F.S., Stereospecific effects of cocaine derivatives on 3H-dopamine uptake correlations with behavioral effects, Subst. Use Misuse, 2, ff5, f98f. 

Katz, J.I., Terry, P., and Witkin, J.M., Comparative behavioral pharmacology and toxicology of cocaine and its ethanol-derived metabolite, cocaine ethyl-ester (cocaethylene), Life Sci., 50, 1351, 1992. 

Glowa J., Fantegrossi W., Lewis D., Matecka D., Rice K., Rothman R. Sustained decrease in cocaine-maintained responding in rhesus monkeys with l-[2]-bis(4-flourophenyl)methoxy[ethyl]-4-(3-hydroxy-3-phenylpropyl)piperazinyldecanoate, a long-acting ester derivative of GBR 12909. J. Med. Chem. 39 4689, 1996. 

Hsin, L.-W., Dersch, C.M., Baumann, M.H. et al. (2002) Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents chiral hydroxyl-containing derivatives of l-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and l-[2-(diphenylmethoxy)ethyl]-4-(3-phe-nylpropyl)piperazine. Journal of Medicinal Chemistry, 45 (6), 1321-1329. 

Banta-Green CJ, Field JA, Chiaia AC, Sudakin DL, Power L, De Montigny L (2009) The spatial epidemiology of cocaine, methamphetamine and 3, 4-methylenedioxymethamphetamine (MDMA) use a demonstration using a population measure of community drug load derived from municipal wastewater. Addiction 104 1874—1880... 

A series of DAT selective 3-phenyltropanes have been reported to have potential for treatment of cocaine abuse [33,36,37]. RTI-336,15 (reuptake IC50 — 4.1 nM) was the most potent among these tropane derivatives in locomotor activity and drug discrimination it was less stimulatory than cocaine, and had the slowest onset and longest duration of action. It also reduced self-administration of cocaine in rats and rhesus monkeys. Interestingly, in rhesus monkeys trained to self-administer cocaine, when coadministrated with either citalopram or sertraline, 15 produced significantly more robust reductions in cocaine self-administration compared with 15 alone [38]. 

Q48 was synthesised to mimic the nerve-blocking activity of cocaine Q49 is indicated for dementia in Alzheimer s disease Q50 was originally derived from the bark of the yew tree... 

According to the Controlled Substances Act, the term narcotic drug refers to more than just opiate drugs it also includes opium, poppy straw, derivatives of opium and opiates, cocaine, coca leaves, and extracts that contain cocaine and ecgonine (the major metabolite of cocaine) and its derivatives. These may be directly or indirectly produced by extraction from substances, by chemical synthesis, or by a combination of both methods. 

Survey data from Colombia show that life-time prevalence of cocaine use increased over the 1992-2004 period, from 1.5 per cent in 199211 to 3.7 per cent in 2004,12 with indications that the increase took place in the late 1990s. Life-time prevalence of cocaine use among youth, aged 10-24, was more than 5 times higher in 2001 than in 1996. This increase may have been associated with the rapid expansion of coca cultivation in Colombia in the late 1990s. A comparison of annual prevalence estimates derived from these studies, with actual annual prevalence data from the new national survey, suggests that cocaine use prevalence... 

The properties and reactions of amino-alcohols, obtained largely by hydrolysis of naturally occurring alkaloids, were investigated primarily for the purposes of structural analysis and the preparation of physiologically active derivatives. Many authors have described acylation of pyrrolizidine alcohols with benzoyl chloride and acetic anhydride (see, e.g., refs. 83 and 101). Trachelanthamidine benzoate and p-aminobenzoate were prepared especially for testing of their physiological activity.102 The p-aminobenzoate was obtained by treatment of trachelanthamidine with p-nitrobenzoyl chloride and subsequent reduction of the nitro group with iron in 20% acetic acid. The compound exhibited an anesthetic activity close to that of cocaine. 

The clinical effects of amphetamine and its derivatives are very similar to those of cocaine, although the euphoria they produces may be less intense but last longer than that due to cocaine. Signs of amphetamine intoxication, toxicity, overdose, sensitization by production of an acute paranoid psychosis, and withdrawal syndrome are all similar to those described above for cocaine. 

A frequently cited example of an important natural-product-derived drag is the neuromuscular blocker d-tubocurarine, derived from the South American plant curare, which was used by South American Indians as an arrow poison (see Chapter 26). Tubocurarine led to the development of decamethonium, which, although structurally dissimilar to tubocurarine, was nevertheless synthesized based on the then prevalent presumption that tubocurarine contained two quaternary nitrogens. Similarly, synthetic local anesthetics, such as lidocaine, benzocaine, and dibucaine, were synthesized to mimic the nerve-blocking effect of cocaine, a natural alkaloid obtained from the leaves of Coca eroxylum, but without the adverse side effects that have led to its abuse. 

It is true that when Coca-Cola was first produced in the mid-1880s it contained cocaine. In fact, the drink derives its name from its two medicinal ingredients — coca leaves and kola nuts. No one really knows how much cocaine Coca-Cola originally contained, but it certainly contained some. By 1902, the amount of cocaine in an ounce of Coca-Cola syrup was as little as 1/400 of a grain, and by 1905 all cocaine was eliminated from the beverage. 

An alternative strategy for the treatment of cocaine addiction involves the use of an anticocaine vaccine. Experiments in rats have demonstrated reduced desire for the drug as well as reduced uptake of cocaine into the brain. The vaccine consists of a synthetic cocaine derivative attached to proteins that trigger immune responses to cocaine. The cocaine derivative is not addictive and brain levels of free cocaine were reduced by 40-60 percent in the study. There are approximately 400,000 cocaine abusers in drug-treatment programs in the United States. 

Because of cocaine s toxicity and addictive properties, a search began for synthetic substitutes for cocaine. In 1905, procaine was synthesized and became the prototypic local anesthetic for half a century. Newer derivatives include mepivacaine and tetracaine (Figure 13.1). Briefly, the SAR of local anesthetics revolves around their hydrophobicity. Association of the drug at hydrophobic sites, such as the sodium channel, is believed to prevent the generation and conductance of a nerve impulse by interfering with sodium permeability (i.e., elevating the threshold for electrical excitability). 

Bicyclic molecules are found in many natural product structures. Cocaine is a derivative of bicyclo[3.2.1]octane in which nitrogen replaces the carbon at the one-carbon bridge. 

Cocaine is an alkaloid derived from the plant Erythroxylon coca and other Erythroxylon species in South America. The leaves contain cocaine as the principal alkaloid, plus a variety of minor alkaloids. Only decocainized coca products are legal in the USA, but some commercially available tea products have been found in the past to contain cocaine in a concentration normally found in coca leaves (about 5 mg of cocaine per 1 g tea-bag). This results in only mild symptoms when package directions to drink a few cups per day are followed, but massive overdosing can result in severe agitation, tachycardia, sweating, and raised blood pressure. 

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