Demethylation of Nicotine

Plant growth and development are complicated biological phenomena, dependent upon genetic and environmental variables. In tobacco products. 

N-Demethylation has been observed also in leaves of Nicotiana alata, a species with a very low nicotine content in its leaves. Schroeter (1958) and Griffith and Griffith (1964) experimented with Nicotiana rustica, a species which normally contains very little nomicotine, and found that nicotine demethylation occurs in both the root and, more rapidly, in the shoot. 

Demethylation and consequent loss of nicotine (Yoshida, 1971) in tobacco leaves during the postharvest period is important commercially, because nomicotine is less toxic than nicotine. These postharvest pro- 

The physiological role or significance of nicotine N-demethylation is unclear. Leete and Bell (1959) administered nicotine to Nico- 

Mothes (1928) related the active demethylating process of nicotine in tobacco plants (Nicotiana tabacum L.) to leaf senescence. Similarly, Mothes et al. (1957) and Schroeter (1966) observed in crude homogenates that older leaves demethylated nicotine much more extensively than did the young leaves. 

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N-Demethylation of Nicotine. Trapping of a Reactive Iminium Species with Cyanide Ion", J. Med. Chem. 1976, 1168-1169. 

This allows an aldol-type reaction with the A-methylpyrrolinium cation, and finally dehydrogenation of the dihydropyridine ring back to a pyridine gives nicotine. Nornicotine is derived by oxidative demethylation of nicotine. Anaba-sine is produced from nicotinic acid and lysine via the A1 -piperidinium cation in an essentially analogous manner (Figure 6.32). A subtle anomaly has been exposed in that a further Nicotiana alkaloid anatabine appears to be derived by... 

In a paper on the mechanism of demethylation of nicotine, Craig et al. used gas chromatO graphy to separate and estimate the alkaloidal products from the reaction mixture. They obtained good separation on a 2 m long column using PEG 20M 5.6 % as stationary phase on Firebrick, at 200°C. The retention times of the individual alkaloids are given in Table 5.4. 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Nornicotine is formed from nicotine during the growth period of the tobacco plant and during senescence (17B06). Enzymatic demethylation of nicotine yields nearly equal quantities of the (-t) and (-) isomers of nornicotine (17B05). 

Bartholomeusz TA, Molinie R, Roscher A, Felpin FX, Gillet F, Lebieton J, et al. Stereo selectivity of the demethylation of nicotine piperidine homologues by Nicotiana plumbaginifolia cell suspension cultures. Phytochemistry 2005 66 (16) 1890-7. 

Figure 2.14a. The accumulation of nicotine. Data are from an average of 21 analyses of plants grown during the summer months. The gene dossis effects a — recessive defective gene and A —dominant active gene for demethylation of nicotine to nomicotine.

Figure 2.14b. The demethylation of nicotine during 3 days after harvest the gene dossis effect is still visible.

Another type of demethylation of nicotine which involves the insertion of the methyl group into the six-membered ring of anabasine will be described in Section 6.7.1. 

Which pathway is taken depends quite decisively on the kind of O-methylation to which norlaudanosoline is subject. If all the hydroxyls are methylated —and this can be brought about by quite unspecific methylating enzymes—then papaverine and its derivatives will be formed. If only certain hydroxyls are methylated in a quite specific manner than the morphine alkaloids will be produced, the most important representatives of which are thebaine, codeine, and morphine. Incidentally, there is good biochemical and genetic evidence that thebaine is first demethylated to codeine and this is then demethylated to morphine, as shown. A similar case with which we are familiar is the demethylation of nicotine to nor-nicotine. 

The aerobic degradation of nicotine produces an A-methylpyrrolidine as the first metabolite by dehydrogenation. This is then hydroxylated at the benzylic carbon atom by an FAD-containing oxidase (Dai et al. 1968), and the y-A-methylaminobutyrate that is produced by fission of the A-methylpyrolidine ring is demethylated by an oxidase to 4-aminobutyrate (Chiribau et al. 2004). 

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]. 

No differences were observed5 in the enzymic oxidation of putrescine and TV-methylputrescine by plant extracts of a cultivar of N. tabacum that had a high nicotine content and one with a high content of nornicotine (7). Thus a high nornicotine (7) content cannot be attributed to direct oxidation of putrescine, and this supports evidence which shows nornicotine (7) to be a demethylation product of nicotine. 

Two examples of unusually large deuterium isotope effects in biological systems have been observed. The oxidative O-demethylation of trideu-teromethoxy anisole showed an isotope effect of —10 in vitro, 3 and the oxidation in vivo of cotinine, a nicotine metabolite, to 3-hydroxycotinine... 

With the advent of tritiated nicotine (and other radioligands) to label neuronal nACh receptors came fairly simple questions such as (a) which is the higher affinity optical isomer of nicotine, ( — )nicotine or (-I- )nicotine, (b) what is the effect of N-demethylation, to afford nomico-tine, and what is the effect of A-methyl homologation, (c) is the pyridine ring of nicotine necessary for high affinity,... 

The alicyclic 3-substituents of nicotine, nornicotine and anabasine are derived from fhe condensation of N-methyl-A -pyrroliniiun ion wifh 1,2-dihydropyridine to give 3,6-dihydronicotine which by loss of hydrogen yields (S)-(-)-nicotine that can undergo demethyl-ation to nornicotine. Anabasine is produced by an analogous series of reactions from A -piperidine. 

Decomposition of this unstable intermediate produces an amine plus either an aldehyde or a ketone. The term used to describe this process depends on which of the two cleavage products one is interested in. If most of the original molecule remains with the amine (e.g. the N-demethylation of olanzapine shown in Figure 9.21), it s considered oxidative N-dealkylation, but if it ends up in the carbonyl-containing fragment (e.g. conversion of a primary phenethy-lamine to a phenylacetaldehyde and ammonia) it would be instead referred to as oxidative deamination. Notably, FMOs can also carry out N-oxidations of secondary and tertiary amines, for example the pyrrolidine nitrogen of nicotine, but not a-hydroxylations to produce the cleavage products that CYPs can provide. ... 

Nomicetine [3-(2-pyrrolidinyl)-pyridine]. Structural formula, see nicotine. C,H,2N2, Mr 148.21, hygroscopic oil with an odor of amines, that rapidly decomposes in the air, bp. 270°C [131 °C (1.5 kPa)] (53-form (alo -88.8° (/f)-form [a]g +86.3°. A tobacco alkaloid and, in contrast to nicotine, hardly volatile in steam. N. occurs in tobacco plants (Nicotiana sp.) and in tobacco, presumably formed by demethyl-ation of nicotine. The (R)-form is also known in Du-boisia hopwoodii. N., like nicotine, is highly toxic... 

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). 

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