D-norNicotine

The repetition of nicotine injections provokes a progressive disappearance of the hypertensive response because the ganglions formerly stimulated are now paralyzed. There results a persistent drop in the arterial pressure accompanied by a tachycardia due to a paralysis of the cardio-parasym-pathetic synapses. However, large doses of nicotine (10 mg./kg.) do not abolish the central emetic action of smaller doses (1-3 mg./kg.) in the cat (72). When convulsions occur (3 mg./kg.), they contribute to the development of a fatal asphyxia by increasing the rate of oxygen consumption and production of carbon dioxide, and by interfering with respiratory movements by spastic contractions of the respiratory muscles. The convulsions are prevented by etherization (5 mg./kg.) (65). d-Nornicotine exerts all the effects of nicotine on the arterial pressure, respiration, sympathetic and parasympathetic ganglia, the heart, etc. However, it is 2.5 times more toxic for the rat (79a). 

To study the formation of NNN in tobacco, plants were analyzed at various stages of growth and curing (23). NNN was not detected prior to harvest or in freshly harvested Burley tobacco but only during and after air curing (0.5-1.1 ppm). Since either nicotine or nornicotine could have been a grecursor to NNN in tobacco, tobacco leaves were fed nicotine-2 - C or nornico-tine-2 -14Q d cured (24). The cured leaves were then analyzed... 

The third species of Duboisia, D. hopwoodi, contains little tropane alkaloid content, but produces mainly nicotine and related alkaloids, e.g. nornicotine (see page 313). Leaves of this plant were chewed by aborigines for their stimulating effects. 

Hu, M.W., W.E. Bondinell, and D. Hoffmann Chemical studies on tobacco smoke. XXll, Synthesis of carbon-14 labeled myosmine, nornicotine, and V -nitrosonomicotine J. Labeled Compd. 10 (1974) 79-88. 

Figure 2.15. Segregation in Nicotiana glauca x N. tabacum hybrids (Blaim and Berbec 1968). The ability to demethylate nicotine is shown in D—the dominant allele from N. glauca. Plants which bear the D gene produce nornicotine expected—75%, observed—77%. Courtesy of the authors and the journal.

The results (Leete and Chedekel, 1974) indicate that 48% of [2- H](-)-nomicotine and 52% [2- C](+)-nomicotine is incorporated from the labeled nicotine. Thus if (+)-nornicotine is formed from (-)-nicotine, the transformation must involve the loss of the hydrogen from C-2 however, almost the same [ HA C]ratio occurs as in the administered mixture of [2 - H](-)-nicotine and [2 2- C](+)-nicotine, which indicates that in N. glauca (+)- and (-)-nicotine are demethylated at similar rates. If the demethylation had been stereospeciflc for (-)-nicotine, the resultant nomi-cotine would have its [ HA C]ratio doubled. This led the authors to propose a scheme for the formation of (+)-nicotine and (-)-nicotine (Figure 6.11). This mechanism accounts for the partial racemization of the nornicotine derived from (-)-nicotine a Cope elimination of nicotine N -oxide (a) would involve one of the hydrogens at C-3, which would provide the unsaturated compound (b). Elimination of water from this hydroxy amine yields the Schiff base (c), which upon hydrolysis yields formaldehyde or other Cl metabolite and the primary amine (d). Cyclization of this intermediate yields (+)- and ( )-nomicotine. Leete and Chedekel presume that these steps are enzyme mediated, and it is to be expected that the final cyclization would yield a preferential amount of (+)- or (-)-nornicotine however, the mechanism which yields (+)-nornicotine from (-)-nicotine remains unknown. 

Whatman KC2F bonded silica gel developed with 0.4 M maltosyl-j8-CD and 0.6 M NaCl in acetonitrile/water (30 70) separated enantiomers of D,L-alanine-/3-naphthylamide, dansyl D,L-leucine, dansyl D,L-valine, D,L-methionine-j8-naphthylamide, and V -(2-naphthylmethyl)nornicotine, and the diastereomers... 

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