Tropane alkaloids cocaine

A special issue of The Journal of Ethnopharmacology in 1981 (Vol. 3, Nos. 2-3) was devoted to coca and cocaine (98). Several other, more general articles on the pharmacological effects of tropane alkaloids have recently appeared (173-185). 

Figure 2.14 Two common tropane alkaloids in Solanum spp. (a) atropine Datura), and (b) cocaine (Erythroxylon coca).

When we look at another tropane alkaloid, cocaine, we get a different scenario. Cocaine is obtained from the coca plant Erythroxylum coca, and is a powerfnl local anaesthetic, bnt now known primarily as a dmg of abuse. There is no chiral centre in the acid portion, which is benzoic acid, but the optical activity of cocaine comes from the alcohol methylecgonine. Because of the ester function in methylecgonine, the tropane system is no longer symmetrical, and the four chiral centres all contribute towards optical activity. 

Tropane alkaloids Tropane Atropine Cocaine Hyoscyamine Scopolamine/ hyoscine... 

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

Tropane alkaloids have a tropane (C4N skeleton -f) nucleus. Structurally, these alkaloids synthesize as postcursors of pyrrolines (Figure 57). a, /3,

tropane alkaloids (e.g., atropine, hyoscyamine, cocaine, tropinone, tropine, littorine and cuscohy-grine) have a strong biological activity, especially as neurotransmitters. 

Cocaine (4.73), the local anesthetic tropane alkaloid of coca leaves, is a potent NE reuptake inhibitor but has no antidepressant activity. 

These are the group of alkaloids that possess a 8-methyl-8-aza-hicyclo [l,2,3]octane or tropane skeleton, e.g. atropine, cocaine and scopolamine. Tropane alkaloids occur mainly in plants from the families Solanaceae and Erythroxylaceae. 8-Aza-hicyclo[l,2,3]octane, i.e. tropane without the 8-methyl group, is known as nortropane. 

Synaptic dopamine transporters are inhibited by various psychotropic alkaloids including the tropane alkaloid cocaine [189, 190], the indole alkaloid ibogaine [191] and by amphetamine (methylphenethylamine) and related compounds [192, 193]. 

Synaptic serotonin (5-hydroxytryptamine) transporters are inhibited by amphetamines, the tropane alkaloids cocaine and ecgonine [194] and by the indole alkaloid ibogaine (12-methoxyibogamine) and its demethylation product ibogamine [191, 195]. Hyperforin is a major antidepressant constituent of St. John s Wort (Hypericum perforatum) and inhibits serotonin uptake by elevating cytosolic Na+ [196]. The additional... 

In these cases the formal //-ammo acid relationship often is a result of late stage condensation or cyclization reactions (e.g. Mannich-type, Pictet-Spengler) within the biosynthesis Typical examples are cocaine and correlated tropane alkaloids, Catharanthus alkaloids or Iboga alkaloids like heyneanine. 

The stimulant narcotic cocaine (benzoylmethylecgonine) from Erythroxylum coca (coca) and other Erythroxylum species (Erythroxylaceae) inhibits serotonin (5HT) and dopamine reuptake. Related bioactive tropane alkaloids from Erythroxylum species include benzoylecgonine, benzoyltropeine (tropine benzoate), cinnamoylcocaine (cinnamoylmethylecgonine) and ecgonine. 

The isolation of atropine, scopolamine, and cocaine occurred long before the development of modern analytical techniques. Gas chromatography was the first instrumental technique available in the field of separation science and thus it is not surprising that these alkaloids were firstly analyzed by GC despite their low volatility. With the advent of capillary columns and the proliferation of various sample introduction and detection methods, GC has evolved as the dominant analytical technique for screening, identification, and quantitation of tropane alkaloids of plant origin as well as in biological fluids. The state-of-the-art of GC analysis of tropane alkaloids has been the subject of two comprehensive reviews [45,58]. We shall therefore mainly focus on publications which have appeared since 2002. 

Gas chromatography of cocaine of plant origin has mainly involved the analysis of the coca plant [77-79]. Identification and quantitation GC methods of minor naturally occurring tropane alkaloids in illicit cocaine samples have also been reviewed [80]. Moore et al. presented an in-depth methodology for the analysis of the coca plant by GC-FID, GC-ECD, and GC-MS for the identification of alkaloids of unknown structure [81]. Recently, Casale et al. [82] have analyzed the seeds from Erythroxylum coca for their alkaloidal content. Several tropane alkaloids were detected and characterized and it appeared that methylecgonidine (MEG) was the primary constituent and not an analytical artifact. 

During a screening of tropane alkaloids in Erythroxylum species from Southern Brazil, Zuanazzi et al. [83] identified a new alkaloid as 3p,6p-ditigloyloxynortropane. The five investigated species were also screened for MEG, tropacocaine, and cocaine. Tropacocaine and MEG were present in two plants but no cocaine was detected in any species. 

Analysis of tropane alkaloids in biological fluids has been developed mostly for cocaine and metabolites. Indeed, it is well recognized that cocaine remains one of the most widely consumed drugs of abuse worldwide. Generally, reversed phase liquid chromatography coupled with UV-VIS detection is employed for these analyses. 

Tropane alkaloids are an important class of natural products possessing different and interesting pharmacological activities. Hyoscyamine (atropine in the racemate form), scopolamine, and cocaine are the major representatives of this class. They are commonly found in plant materials, mainly in genera belonging to three families Solanaceae, Erythroxylaceae, and Convolvulaceae. The importance of these compounds requires that there are accurate analytical methods for their determination in plants and in biological matrices. This chapter describes the state-of-the-art of analytical procedures (extraction and analysis) for analyzing tropane alkaloids. 

The tropane alkaloids extracted from the leaves can be used to prepare pure cocaine. One route which is possible is as follows. The alkaloids are hydrolysed by using 1 M hydrochloric acid, which produces ecgonine. The latter is treated with 10% boron trichloride in methanol, to give ecgonine methyl ester, which is then reacted with benzoyl chloride, producing cocaine. 

The tropane alkaloids hyoscyamine and scopolamine (Fig. 3a) fnnction as acetylcholine receptor antagonists and are nsed chnically as parasympatholytics. The illegal drug cocaine also... 

Putrescine A-methyltransferase (PMT, EC 2.1.1.53) catalyses the first specific step in the biosynthesis of tropane alkaloids, cocaine and nicotine [123]. Putrescine is methylated by PMT via SAM (S-adenosylmethionine) transferring the methyl group from SAM to an amino group of putrescine. Fig. (1). This enzyme has been isolated from roots of both Nicotiana tabacum and D. stramonium [124], and the activity of this enzyme is restricted to the roots of Solanaceous species corroborated by results describing a root pericycle-specific activity in A. belladonna [125]. Nevertheless, more recently, a low mRNA pmt transcript level in leaves of N. tabacum, with a rise in transcript level after mechanical wounding has been detected [126]. 

Alkaloids are classified according to their heterocyclic rings. For example, cocaine, a central nervous system stimulant, and atropine, a muscle relaxant, are examples of the tropane alkaloids in which a nitrogen appears in a bridge of a seven-membered ring structure. Nicotine, the addictive and toxic component of tobacco, is an example of the pyridine alkaloids in which a nitrogen appears as a member of a six atom aromatic ring. (Nicotine is an effective insecticide.) The addictive... 

In a recent investigation, Kibayashi et al. have used a nitroso Diels-Alder strategy in the synthesis of tropane alkaloids (Scheme 3-VIII).27 The initial cycloaddition of a-chloronitrosocyclohexane with 6-benzy-loxy-l,3-cycloheptadiene showed a 4 1 facial selectivity. The major isomer of this cycloaddition could be converted to pseudotropane and tropa-cocaine by a straightforward sequence of steps. 

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