Nornicotine

Proline and ornithine would also appear to be the most probable amino acid precursors of 1-hyoscyamine, and, as such, the source of the nitrogen of the tropane nucleus. The biosynthesis of the tropic acid half of the molecule has not yet received attention. Such investigations as have been made up to the present have been based upon Robinson s (113) proposed tropinone synthesis from ornithine plus acetone, and have been principally concerned with the identification of the original nitrogenous precursor. 

The proposed synthesis supposes the following sequence of reactions  

Alternatively, further oxidation of the 7-aminobutyraldehyde to succindialdehyde is proposed, followed by condensation wdth methylamine and acetone. 

Hygrine occurs in Erythroxylon truxillense Rusby leaves in extractable quantities, but not in those of other tropane-forming species. It could be equally well regarded either as an intermediate substance or an unmanageable side product. Difficulties in realizing its oxidation have led to the suggestion of yet another possible precursor of hyoscyamine in diamino-adipic acid. When this is done the difficulty of the intermediate oxidation disappears, but the origin of the diaminoacid puts another in its place. 

In a further experiment, it was shown that a 5% glycerol extract of belladonna roots released ammonia from putrescine on incubation at 25°C. for 24 hours in the presence of toluene as antiseptic. Boiling, or a M/1000 cyanide solution, completely inhibited the reaction which may therefore be ascribed to an oxidase. A simultaneous increase in carbonyl content in the digests was observed by formation of 2, 4-dinitrophenylhydrazones and estimation of the color produced on adding sodium hydroxide. Carbonyl formation was also suppressed by boiling or by a M/1000 cyanide solution. Positive results were obtained with etiolated shoots as well as roots, but not with green leaves. 

---

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). 

In a study for precursor determination, we stem-fed individual Burley leaves with nicotine-2 - C or nornicotine-2 - C (29). Subsequently, the leaves were air cured, dried and analyzed for NNN and NNN- C. Recovery of the p-activity in the form of NNN- C amounted to 0.009% and 0.007%, respectively of the stem-fed label. This demonstrates that both alkaloids give rise to NNN. More importantly, it points to the fact that the tertiary amine, nicotine, which constitutes 0.5-2.6% of commercial tobaccos (26,27), is the major precursor for the carcinogenic tobacco-specific NNN, while the secondary amine, nornicotine is of lesser importance because it amounts to only 0.005-0.06% in tobacco (Figure 8). 

Figure 8, Conversion of labeled nicotine and nornicotine during curing.

Jacob, P. Ill (1982) Resolution of ( )-5-Bromonornicotine. Synthesis of (R) and (S)-Nornicotine of High Enantiomeric Purity. Journal of Organic Chemistry, 47, 4165-4167. 

Baxendale, I.R., Brusotti, G., Matsuoka, M., Ley, S.V. (2002) Synthesis of Nornicotine, Nicotine, and Other Functionalised Derivatives Using Solid-supported Reagents and Scavengers. Journal of the Chemical Society Perkin Transactions 1, 143-154. 

Nicotine, concentration in plants, 2 76. See also Nornicotine S-(-)-Nicotine, 2 83... 

Nornicotine, 2 83. See also Nicotine ( j-AT-Norprotosinomenine, 2 90 Norrish mechanisms, 23 376 Norsk Hydro, magnesium manufacturing by, 15 332-334 Norsorex, 22 363-364 North America... 

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. 

Siminszky B, Gavilano LB, Chakrabarti M (2007) Evolution of nicotine N-demethylaze genes and their use in reducing nornicotine levels in tobacco. Recent Adv Tob Sci 33 27-38 Sisson VA, Severson RE (1990) Alkaloid composition of the Nicotiana species. Beitr Takforsch 14 327-340... 

Dwoskin LP, Buxton ST, JeweU AL, Crooks PA (1993) S(-)-Nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices, J Neurochem 60 2167-2174... 

Yamanaka H, Nakajima M, Fukami T, Sakai H, Nakamura A, Katoh M, Takamiya M, Aoki Y, Yokoi T (2005b) CYP2A6 AND CYP2B6 are involved in nornicotine formation from nicotine in humans interindividual differences in these contributions. Drug Metab Dispos 33 1811-1818... 

Starting from nornicotine, we were able to demonstrate the rapid construction of a small collection of nicotine derivatives using a range of readily available monomers (Scheme 2.81). In this way we were able to create compounds to probe... 

Nicotinic acid (Figure 29) provides alkaloids with the pyridine nucleus in the synthesizing process. This nucleus appears in such alkaloids as anabasine, anatabine, nicotine, nornicotine, ricine and arecoline. Moreover, many alkaloids... 

Figure 47. Scheme of nicotine and nornicotine synthesis pathway. 

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. 

---