The Tobacco Alkaloids

The presence of nicotine has recently been reported in Dvboisia myoporoides R. Br. (41) and in Mucuna pruriens DC. (42). The work described by Dawson on tomato-tobacco grafts has been repeated with Nicotiana macrophylla Spreng, N. longiflora Cav., N. rusbyi Britton, N, trigonophylla Dun., and N. glutinosa L. his results have been confirmed (43). 

The biogenesis of nicotine has been studied in the plant with the aid of radioactive tracers. It was first shown that sodium formate is a precursor of the iV-methyl group of nicotine, but that methionine is a more immediate precursor since when these substances labeled with C are fed to the plant, the yield in radioactivity is greater with methionine than with formate (44). It was concluded that the methy-lation by methionine involved a true transmethylation and that the methyl group was not transferred via an intermediate oxidation to formate (44). This view found support in the results of an experiment involving the use of methionine with its methyl group doubly labeled with and deuterium. In this experiment, the ratio of the and 

It has been established independently and simultaneously in two laboratories that ornithine is the precursor of the pyrrolidine ring in nicotine (51, 52). Adult plants of N. rustica L. maintained 14 days in hydroponic solutions containing omithine-2-C are found to contain radioactive nicotine. After oxidation, carbon 2 of the pyrrolidine ring is isolated as nicotinic acid and carbons 3, 4, and 5 are isolated as barium carbonate. Nicotinic acid contains half the radioactivity and barium carbonate the other half. Decarboxylation of the nicotinic acid shows that the radioactivity is exclusively located in the carboxylic group. It is highly probable that the second half of the radioactivity is located on carbon 5, but the separation of this carbon from carbons 3 and 4 has not been effected (51, 52). 

Anabasine (3-pyridyl-2-piperidine) appears to be the sole constituent of N. glauca R. Grah., and this plant has been used for the study of the biogenesis of the alkaloid. Anabasine isolated from N. glauca cultured in hydroponic solution containing lysine-2-C hydrochloride is radioactive (53). The alkaloid when oxidized with nitric acid gives nicotinic acid which by decarboxylation yields pyridine and carbon dioxide isolated as barium carbonate. Whereas the activity of anabasine is 

These results point out the difference that can exist between real biological conditions as they are found in the plant, and those obtaining in so-called pseudophysiological syntheses. Although lysine in the tobacco plant is not the preeursor of the pyridine ring, Schopf has shown that under pseudophysiological conditions lysine is converted via A -piperideine into anabasine (60). 

Recent intensive interest in the physiological effects of habitual smoking has resulted in the publication of thorough reviews of the chemistry of tobacco constituents 76, 77). The chemistry of nicotine and related alkaloids including biosynthetic aspects has been surveyed 78) and the chemistry of pyrolysis products of tobacco alkaloids in smoke has been reviewed (79). 

Nicotine has been found in Sem/pervivum arachnoideum L. 80), in Erythroxylum coca Lam. 81), in Duboisia myoporoides R.Br. grown on 

The IR-spectra of 41 tobacco alkaloids and related compounds have been tabulated (S5). Nornicotine, nicotine, myosmine, nicotyrine, anabasine, anatabine, and dihydronicotyrine were separated from an extract of tobacco alkaloids by countercurrent partition (86). Thin-layer chromatography has been used to separate nicotine, nornicotine, anabasine, and nicotyrine (57). The use of gas chromatography to separate tobacco alkaloids has been studied. The retention times of 11 tobacco alkaloids on polyethylene glycol columns has been reported (88) and the effect of the column packing on the retention times of pyridine bases has been described (89). Mixtures containing pyrrolidine, piperidine, pyridine, and various alkylated pyridines have been separated using programed temperature control (90). 

Ethyl nicotinate heated with 3-benzylidenepropylamine gave the amide (LVIII) which with phosphorus oxychloride gave 2-(3-pyridyl)-3-benzylidene-l-pyrroline (LIX). LIX was reduced with sodium 

3-Bromopyridine with butyllithium and l-methyl-2-p3irrolidone gave iV-methylmyosmine which when heated with formic acid and fused potassium formate gave d -nicotine (93). 

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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). 

The useful reviews of chemical and biological work on the tobacco alkaloids by Jackson,Roark, ( ) and Markwood issued in the United States have been referred to already and to these may be added that of Holman published in the United Kingdom, and the handbook of reference tables on the biochemistry of tobacco issued by Smirnov et al. in Russia. 

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

Figure 7. Some nitrosamines which can be derived from the tobacco alkaloids.

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. 

Leete E (1983) Biosynthesis and metabohsm of the tobacco alkaloids. In Pelletier SW (ed) Alkaloids chemical and biological perspectives, WUey, New York, pp 85-152 Leong JW, Dore ND, SheUey K, Holt EJ, Laing lA, Palmer LJ, LeSouef PN (1998) The elimination half-hfe of urinary cotinine in children of tobacco-smoking mothers, Pulm Pharmacol Ther ll(4) 287-290... 

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. 

Solenopsis (Diplorhoptrum) conjurata and some other thief ants contain indo-lizidines and/or piperidines (Tables I and II). (5Z,8 )-3-Heptyl-5-methylpyr-rolizidine (48) has also been shown to be contained in the thief ant Solenopsis xenovenenum (Table IV). The poison glands of Aphaenogaster fulva and A. tennesseensis contain the tobacco alkaloid anabaseine (8), which functions as an attractant in A. fulva (Table I) (26). 

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. 

NT562 Leete, E. Biosynthesis and metabolism NT572 of the tobacco alkaloids. Alkaloids ... 

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-... 

The tobacco alkaloids, especially nicotine, are derived from nicotinic acid (see page 311) but also contain a pyrrolidine ring system derived from ornithine as a portion of their structure. 

The tobacco alkaloid anabasine (37) has been synthesized from 3-pyridyl-lithium (prepared from 3-bromopyridine and t-butyl-lithium) by reaction with A piperideine at —120 °C.46... 

The in vitro and in vivo metabolism of the tobacco alkaloids has been thoroughly reviewed in recent years (159), and their microbial transformations have also been discussed (11). A detailed discussion of the biosynthesis and metabolism of tobacco alkaloids supplementary to reference 159 has also been presented (160). 

Trevor, A.J. and Castagnoli, N., Jr. Liver and lung microsomal metabolism of the tobacco alkaloid -nicotyrine. Chem Res Toxicol 2 282-287, 1989. 

A versatile short synthesis of the tobacco alkaloids has been developed (G.F. Alberici et al., Tetrahedron Letters, 1983,... 

Furthermore, nicotine and benzothiazol were specific contaminants of the seepage water, accompanied by their oxidation products cotinine and benzothiazolones. The tobacco alkaloid cotinine, which is also a mammal metabolite of nicotine, appeared in minor concentrations. Concentrations of nicotine and cotinine ranged from 550 to 710 pg/L and from 90 to 180 pg/L, respectively. As compared to the seepage water samples no signficant reduction of the concentrations in the leakage water was observed. The origin of benzothiazolone can be attributed either to an oxidation of benzothiazol or to the hydrolysis of substituted benzothiazols like 2-methylthiobenzothiazol, a common rubber additive. 

Qiemically the tobacco alkaloids are based on pyridine with, usually, a secondary or tertiary alicyclic base as the 3-substituent (Figure 1), in some cases the 3-substituent is aromatic or has been modified by the presence of double bonds or a carbonyl functional group. The ratio of these alkaloids in various tobacum strains varies and in certain strains the related secondary amines nornicotine or... 

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