Nicotine, nomicotine and anabasine

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. ... 

The substituted pyridine derivatives are biologically active compounds. Nicotine, nomicotine and anabasine are natural insecticides known for a long time. Pyridine-2-thiol-l-oxide and pyridine-nitrile (2,6-dichloro-4-phenylpyridine-... 

Table 3. Acute toxicity of nicotine, nomicotine and anabasine in various species.

In this way, generally after localisation through the fluorescence of the substances themselves, determinations have been carried out of coumarin derivatives, following chromatographic separation from lemon and grapefruit oils [729] quinoxaline derivatives of 2-ketoacids [651] benzo-(a)-pyrene [599] and vitamin Bg factors [702]. Cortisol [228] and aldosterone [229] which had been extracted from urine and purified by TLC, have been localised with the help of a reference chromatogram and then determined fluorometrically after treatment with sulphuric acid. After extraction from the thin layer, nicotine, nomicotine and anabasine could be determined phosphorimetrically (see p. 141) with a relative standard deviation of 6% [761]. 

The production of toxins is only one aspect of plant defense strategy. As a result of the persistent battle of plants and herbivores, many optimized phenotypes have evolved, such as the preferential accumulation of alkaloids in tissues with a pattern that is consistent with predictions of optimal defense theory,65 i.e., the defense metabolites are allocated preferentially to tissues with a high probability of attack.66 The inducibility of pathways leading to plant secondary compounds as a strategy to minimize the costs of plant defense is a result of permanent optimization. One of a few examples of inducible alkaloid biosynthesis is the different Nicotiana species that exhibit dramatic wound-induced increases of nicotine, nomicotine, or anabasine.67... 

Physiology biosynthesis Like the tropane alkaloids, T. a. are formed in the roots and transported to the aboveground parts for storage by the plant s phloem system. In some sorts of tobacco plants a part of the nicotine is demethylated to nomicotine during transport to the shoot. Nomicotine and anabasine are often the main alkaloids in the so-called nicotine-poor tobacco plant types. The T. a. are formed biogenetically from nicotinic acid, made available via the pyridine nucleotide cycle (see nicotinamide), and a pyrrolidine or piperidine building block (figure). In the case of nicotine, like for the tropane alkaloids, Al-methylpyr-roline is an intermediate, in the biosynthesis of anabasine the intermediate is a piperidine derived from the amino acid lysine (see piperidine alkaloids). 

Pyridine, piperidine and pyrrolidone alkaloids Arg, Lys, Orn, nicotinic acid Tobacco leaves Nicotine, nomicotine, anatabine, anabasine... 

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. 

Nicotinoids. Nicotine from tobacco was one of the earliest insecticides and was recommended for use in 1763 as a tea for the destruction of aphids (1,20). Nicotine [54-11 -3], L-l-methyl-2-(3 -pyridyl)pyrrolidine (1) (bp 247°C, d 1.009), is found in the leaves of Nicotiana tobacum and N. rustica (Solanaceae) in amounts ranging from 2 to 14%, and also is found in Duboisia hopwoodii and in Aesclepias syriaca. It occurs as the principal alkaloid along with small amounts of 12 other alkaloids of which nomicotine [494-97-3], 2-(3,-pyridyl)pyrrolidine (2) (bp 270°C, d 1.07 g/mL), and anabasine [494-52-0], l-2-(3 -pyridyl)piperidiae (3) (bp 281°C, d 1.048), are of insecticidal importance (see Alkaloids). Nomicotine occurs as both the D and L forms, the former in D. hopn oodii and the latter commonly predominating in Nicotiana. Anabasine is the chief alkaloid of Anabasis aphylla, where it occurs from 1—2% in the shoots and is found to ca 1% in Nicotianaglauca. 

Nomicotine, in which the N-methyl is replaced by hydrogen, is somewhat less potent and active than nicotine in most assays (102). R- and S-nomicotine are equipotent with R-(+)-nicotine,the less active, unnatural enantiomer, in a rat brain membrane-binding assay (103). In that study, S-(-)-nicotinewas 13 times more potent than its R- enantiomer. Replacement of the N-methyl of nicotine with ethyl or n-propyl eauses an exponential loss of peripheral nicotinic effect (102). Anabasine (51), a relatively minor alkaloidal constituent of tobacco, demonstrated approximately 1/10 the affinity of nicotine in a binding assay (104). A synthetic azetidine congener (52) of nicotine binds with the same affinity as nicotine to rat brain membrane tissue, and it displayed a greater potency than nicotine in a rat behavioral assay (105). Evaluation of a series of 6-substituted nicotine derivatives (53) led to the conclusion that affinity for rat brain... 

Pyridine alkaloids are compounds with a pyridine nucleus and a pyrrolidine or piperidine unit. The pyrrolidine ring appears in nicotine and the piperidine ring in anabasine. Typical alkaloids from this group are nomicotine and anatabine. The a of pyridine alkaloids is nicotinic acid, the p is dihydro-nicotinic acid, the q> is 1,2-dihydropyridine (Figure 2.41). The A is nicotine and its P is nomicotine. ... 

Cestroideae. Nomicotine (major alkaloid), nicotine, and anabasine were detected in Salpiglossis sinuata (Salpiglossis clade) (Schroter 1958, 1963). The same alkaloids were found as constituents of Streptosolen jamesonii (BrowaUieae clade) (Schroter 1963). Nicotine and its nor congener were isolated also from the leaves of Cestrum diurnum and C. nocturnum (Cestreae clade), in addition cotinine and myosmine from the latter species only. This was the first report on the occurrence of cotinine and myosmine outside of the genus Nicotiana. However, all these alkaloids were present in such small concentrations that the toxicity attributed to both Cestrum species should be based on different constituents (steroidal saponins, see Sect. 7.7) (Halim et al. 1971). 

Potential Physiological Significance for Nicotinoid-prodncing Plants Themselves. Nicotine, nomicotine, anabasine, and anatabine were shown to produce a cumulative inhibition of the invertase activity of Nicotiana glauca. The alkaloids may have a role in the functional behaviour of this enzyme which cleaves... 

Figure 2.5. Chromatographic patterns of N. debneyi, N. glauca, and N. suaveolens together with the amphiploids N. debneyi-glauca (DDGG) and N. suaveolens-glauca. No—nomicotine A—anabasine N—nicotine and Ul, U2, U6—unknowns (Smith and Abashian, 1%3). Courtesy of the American Journal of Botany.

Nicotine in tobacco is always accompanied by three other prominent alkaloids nomicotine, (S)-2-(3-pyridyl)pyrrolidone, anatabine, (S)-2-(pyrid-3-yl)-l,2,5,6-tertrahydropyridine and anabasine, (S)-2-(pyrid-3-yl)piperidine (10-7). Apart from these main alkaloids, more than 20 other minor tobacco alkaloids (10-8) have been identihed. 

The pyridine alkaloids anabasine (1), nicotine (2), ricinine (3), nomicotine (4) and trigonelline (5) form an important group of natural products. Thus anabasine (1) is extracted on a large scale in the Soviet Union (56MI20900) and functions as an insecticide with acute and subacute toxicity. Nicotine (2) has been used as an anthelmintic but more widely as an agricultural insecticide, functioning as a contact poison when combined with oleic acid... 

Labeling by deuterium or carbon-13 always leads to unequivocal signal identification of specific carbon atoms [600, 602, 640], After the administration of [5,6-14C-13C2]nicotinic acid to Nicotiana tabacum and N. glauca labeled anabasine anatabine, nicotine and nomicotine could be isolated. The satellites at the resonances of the labeled natural products helped to complete the signal assignments of the 13C NMR spectra of these alkaloids [602]. 

Klus et al. (15A32) measured several ETS-related TSNAs in indoor air of an 83-m office under various smoking conditions. NNN varied from 0.7 to 6 pg/L, NNK varied from 0.2 to 10.7 pg/L. They found no correlation with the carbon monoxide levels. Tricker et al. (3945) reported that nicotine was not V-nitrosated to NNN under simulated gastric conditions. However, nomicotine, anabasine, and anatabine were V-nitrosated to NNN, NAB, and NAT, respectively, under such conditions. They also reported that NNK decomposed slightly under these conditions. 

Watson et al. 1983). Nicotine also occurs in many remotely related plants such as club mosses. This is possible since the precursor nicotinic acid (vitamin B3) is of widespread distribution in the plant family. Pure nicotine is a colourless oily alkaloid, while salts of nicotine are readily water soluble. The prime pharmacological alkaloid in tobacco is L-nicotine (0.5-10%), along with nomicotine, anabasine and nicotyrine. Structurally nicotine consists of a simple linking of pyridine and pyrollidine rings. 

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