Tobacco alkaloids nicotine

The nicotinic receptor (nAChR) comprises a family of receptor subtypes that respond to the neurotransmitter acetylcholine (ACh) and the tobacco alkaloid nicotine. 

Chiribau CB, C Sandu, M Eraaije, E Schiltz, R Bradsch (2004) A novel y-A-methylaminohutyrate demethyl-ating oxidase involved in catabolism of the tobacco alkaloid nicotine by Arthrobacter nicotinovorans pAOl. Eur JBiochem 271 4677-4684. 

At a low concentration, the tobacco alkaloid nicotine acts as a ganglionic stimulant by causing a partial depolarization via activation of ganglionic cholinocep-tors (p. 108). A similar action is evident at diverse other neural sites, considered below in more detail. 

Kleinsasser, N. H., Sassen, A. W., Semmler, M. P., Harreus, U. A., Licht, A.-K. and Richter, E. 2005. The tobacco alkaloid nicotine demonstrates genotoxicity in human tonsillar tissue and lymphocytes. Toxicological Sciences, 86(2) 309-317. 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

The tobacco alkaloid nicotine (96) (B-67MI10702) is insecticidal by virtue of its action on the acetylcholine receptor. It was used widely as an aphicide, especially as a fumigant. Another natural product thought to act on the same receptor is the 1,2-dithiolane nereistoxin (97) (B-72MI10703), isolated from the marine annelid Lumbriconereis heteropoda. The active form has been shown to be the ring opened dithiol (98), and the protected form of it, cartap (99), is sold as a rice insecticide. The 1,2,3-trithiane thiocyclam (100) (72SAP7007824) is also active, presumably because of metabolic conversion to (98). 

Acetylcholine receptors. There are numerous receptors for ACh (Fig. 12—10), of which the major subtypes are nicotinic and muscarinic subtypes of cholinergic receptors. Classically, muscarinic receptors are simulated by the mushroom alkaloid muscarine and nicotinic receptors by the tobacco alkaloid nicotine. Nictotinic receptors are all ligand-gated, rapid-onset, and excitatory ion channels, which are blocked by curare. Muscarinic receptors, by contrast, are G protein—linked, can be excitatory or inhib-... 

Bush determined the four most important tobacco alkaloids (nicotine, nornicotine, anabasine and anatabine) using a 10 % DC 550 packed column on Chromosorb 60-80, and using isoquinoline as an internal standard. The alkaloids were extracted with benzene-chloroform (9 1) after treatment of the tobacco sample (1 g) with bariumhydroxide and water. The organic phase was concentrated and used for the gas chromatographic determination. Because of the great differences in the amounts of the minor alkaloids and nicotine in most tobacco samples, two extractions, each with an appropriate amount of internal standard, were required for a complete assay. The precision of the quantitative analysis on tobacco samples of different alkaloids is given in Table 5.6. 

A classic example of a ligand-gated ion channel from the cys-loop superfamily is the nAChR. The nicotinic AChRs are named so because they can be activated by the tobacco alkaloid nicotine in the same way they are activated by ACh. It should be mentioned that the muscarinic A.ChR s, which respond to the alkaloid muscarine, are not ion channels, and therefore not discussed in this chapter. The nAChR is made up of five subunits (al, pi, 7, 5, and e) with two binding sites for ACh (Figures 16.6B and 16.9). The nAChRs are expressed in nerves and skeletal muscle (but not smooth muscle) and play an important role in the fast synaptic transmission in synaptic neuronal-neuronal and neuromuscular junctions. nAChR is a nonselective cation channel that allows the flow of many cations, but not anions. After ACh binds to the nAChR it allows Na" " and also Ca " ", to flow down their electrochemical gradient into the cell, which depolarizes the cell membrane and generates an action potential (Figure 16.6B). 

Among the tobacco alkaloids, nicotine and anabasine are the major components. All tobacco alkaloids are toxic. The toxicity of nicotine and anabasine is discussed below under separate headings. There are also other harmful substances that are not alkaloids. These include nitrosamines, neophytadiene, solanesol, polyphenols, hydrocarbons, and steroids. 

The role of nicotine in tobacco carcinogenesis is not yet fully understood (see the preceding section, Tobacco Alkaloids ). Nicotine is a precursor of N -nitrosonomicotine [16543-55-8], which is a suspected lung carcinogen (Hoffmann et al. 

Nicotinoids with Basic Pyrrolidine or Piperidine Moiety. Nicotinoids are (i) congeners of nicotine, usually minor alkaloids but the term also includes (ii) the principal tobacco alkaloid, nicotine itself. From the structural point of view the nicotinoids may be divided into five groups (Figs. 3.8 and 3.9) ... 

Fig. 3.10 Biosynthesis of the major tobacco alkaloids nicotine, anabasine, and anatabine...

A more typical example of the biosynthesis of an alkaloid is given by the tobacco alkaloid nicotine, which has been shown to be derived from nicotinic acid and ornithine. Its biosynthesis has been studied in detail. A dihydropyridine is an intermediate because if nicotinic acid is labelled at C-6, that label is lost during condensation. The methyl group in the pyrrole ring comes from S-adenosyl methionine (Figure 9.4). In the final stage, the labelled hydrogen is lost as H to NADP+. Anabasine (another tobacco alkaloid) is produced similarly from nicotinic acid and lysine. 

Tobacco Alkaloids. The relatively small number of alkaloids derived from nicotinic acid (27) (the tobacco alkaloids) are obtained from plants of significant commercial value and have been extensively studied. They are distinguished from the bases derived from ornithine (23) and, in particular, lysine (24), since the six-membered aromatic substituted pyridine nucleus common to these bases apparendy is not derived from (24). 

There are four broad classes of alkaloids whose general economic aspects are important (/) the opiates such as morphine and codeine (2, R = H and R = CH3, respectively) (2) cocaine (11) (both Hcit and iUicit) (2) caffeine (16) and related bases in coffee and tea, and (4) the tobacco alkaloids such as nicotine (21). 

Tobacco and its alkaloids have long ceased to have any therapeutic importance, but their extensive use as insecticides and the demand for nicotine for the manufacture of nicotinic acid have stimulated interest in processes of extraction and methods of estimation. On the latter subject there is a voluminous literature, of which critical resumes have been published by various authors.Recent work on this subject has been specially concerned with (1) the development of miero- and semi-miero-methods suitable for estimating nieotine in tobacco smoke and the distribution of nieotine on sprayed garden produce, in treated soils and in tobaeeo leaves,(2) the study of conditions necessary to ensure satisfactory results in using particular processes, " and (3) methods of separation and estimation of nicotine, nomicotine and anabasine in mixtures of these bases. ) In the United States and in Russia considerable interest is being shown in the cultivation of types of tobacco rich in nicotine, in finding new industrial uses for tobacco and its alkaloids, and in possible by-products from tobacco plants such as citric and malic acids, i " Surveys of information on tobacco alkaloids have been published by Jackson, i Marion and Spath and Kuffner. ... 

Precursors and Formation. Tobaccos used for commercial products in the U.S.A, contain between 0,5 and 2,7% alkaloids. Nicotine constitutes 85-95% of the total alkaloids (14,26,27). Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine and N -formylnornicotine (Figure 6), Several of these alkaloids are secondary and tertiary amines and, as such, amenable to N-nitrosation. The N-nitrosated alkaloids identified to date in tobacco and tobacco smoke include N -nitrosonornico-tine (NNN), 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and N -nitrosoanatabine (NAT Figure 7). In model experiments, nitrosation of nicotine also yielded 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA 28). 

The primary psychoactive alkaloid in tobacco is nicotine (figure 4.9), occuring between 0.6 and 9.0% (Robbers et al. 1996 Gruenwald et al. 1998). Other alkaloids include nornicotine, N-formylnornicotine, cotinine, myosmin, )S-nicotyrine, anabasine, and nicotellin. Nicotine alone can produce the effects commonly associated with tobacco use, but other tobacco alkaloids are likely to contribute. 

This section focnses on the nse of nicotine and cotinine and other tobacco alkaloids as biomarkers of tobacco exposure. Other potential biomarkers of exposure to the particulate or gas phase of tobacco smoke are described in the review papers cited above. 

The primary alkaloid in tobacco is nicotine, but tobacco also contains small amounts of minor alkaloids such as anabasine, anatabine, myosmine, and others. The minor alkaloids are absorbed systemically and can be measured in the urine of smokers and users of smokeless tobacco (Jacob et al. 1999). The measurement of minor alkaloids is a way to quantitate tobacco use when a person is also taking in pure nicotine from a nicotine medication or a nontobacco nicotine delivery system. This method has been used to assess tobacco abstinence in clinical trials of smoking cessation with treatment by nicotine medications (Jacob et al. 2002). 

Tobacco use is primarily due to psychopharmacological effects of nicotine (Henningfleld et al. 2006). Nicotine is a tobacco alkaloid, a basic substance that contains a cychc nitrogenous nucleus. In Nicotiana plants, most alkaloids are 3-pyridyl derivatives In cured leaf of Maryland Robinson Medium Broadleaf, 24 pyridine derivatives were identified, including nicotine, nomicotine, anabasine, oxynicotine, myosmine, 3-acetylpyridine, 2,3 -dipyridyl, iticotinamide, anatabine, nicotinic acid, and unidentified pyridine alkaloids of derivatives thereof (Tso 1990). Nicotine is the principal alkaloid in commercial tobacco (this was confirmed in 34 out of 65 Nicotiana species) nomicotine, rather than nicotine, appears to be the main alkaloid in 19 out of 65 species and anabasine is the third most important. In addition to the above-mentioned principal and minor alkaloids, the presence of many trace amounts of new alkaloids or their derivatives were frequently reported, including, for example, 2.4 -dipyridyl, 4,4 -dipyridyl, N -formylanabasine, A -formylanatabine, N -acetylanatabine, N -hexanoyl-nomicotine, N -octanoyl-nomicotine, T-(6-hydroxyoctanoyl) nomicotine, and l -(7-hydroxyoctanoyl) nor-nicotine. 

While cigarette sales in the USA declined 18%, from 21 billion packs in 2000 to 17.4 billion packs in 2007, during the same time period sales of other products, such as moist snuff, increased by 1.10 billion cigarette pack equivalents (Connolly and Alpert 2008). In the USA, the most common smokeless tobacco (ST) products are chewing tobacco (loose leaf, plug, and twist), moist snuff, and dry snuff. Many other forms of smokeless tobacco that are used globally were described in an lARC monograph (lARC 2007). All ST products contain nicotine and other tobacco alkaloids that are inherent to tobacco leaf. 

The predominant alkaloid fonnd in tobacco is (—)-nicotine other molecnles found in tissnes of smokers are either present in tobacco smoke or are metabolites of nicotine, inclnding (4-)-nicotine, (-P)-nomicotine, (—)-nomicotine and (—)-cotinine, the major metabolite (Clark et al. 1965). In animals trained to recognise the stunnlns produced by (—)-nicotine, (-P)-nicotine fully substituted for (—)-nicotine but was about one-tenth as potent. There was no stereoselectivity in responding observed with the metabolite nomicotine and both (-p) and (—)-isomers fully substituted for nicotine but again were 10-fold less potent. (—)-Cotinine also substitnted for nicotine at very high doses bnt this conld be explained by the presence of small amounts of (—)-nicotine in the sample of cotinine (Goldberg et al. 1989). 

The most direct way to help people manage the symptoms of nicotine dependence and withdrawal is therapeutic use of nicotine replacement therapy (NRT) (Fiore et al. 2000 Henningfleld 1995 American Psychiatric Association 1996). Nicotine has been shown to be the main active ingredient in tobacco that causes and sustains addiction to tobacco (US Department of Health and Human Services 1988). Laboratory research has demonstrated that animals (Goldberg et al. 1983) and humans (Henningfleld et al. 1983) who have been chronically exposed to nicotine or tobacco smoke will self-administer nicotine infusions. It should be noted that other constituents in tobacco, such as MAO inhibitors (Fowler et al. 1996a, b), may also play a role in tobacco dependence. The potential role of alkaloids other than nicotine has not been ruled out. This is consistent with the observations that what has been termed tobacco delivered nicotine is more addictive and toxic than formulations provided by nicotine replacement medications (Royal College of Physicians 2000). 

Nicotine is a plant product, particularly abundant in tobacco. Plant products containing ring structures and at least one nitrogen atom are known as alkaloids. Nicotine is one of the most addictive substances known ask any cigarette smoker who has tried to quit. 

The nicotinic ACh receptor responds to the alkaloid nicotine contained in tobacco (many of the physiological effects of nicotine are based on this). The nicotinic receptor is ionotropic. Its properties are discussed in greater detail on p. 222. 

A. Crooks. Nornicotine, a nicotine metabolite and tobacco alkaloid desensitization of nicotinic receptor-stimulated dopamine release from rat striatum. Eur J Pharmacol 2001 428(1) 69-79. 

NT437 Leete, E., and S. A. Slattery. Incorporation of (2- C) nicotinic acid into the tobacco alkaloids. Biosynthesis of anatabine and alpha, beta-dipyridyl. J Am Chem Soc 1976 98 6326. 

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