Piperidine alkaloids nicotine

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]. 

The rather similar alkaloids anabasine and anatabine come from different biosynthetic pathways. Labelling experiments outlined below show the origin of one carbon atom from lysine and others from nicotinic acid. Suggest detailed pathways. (Hint. Nicotinic acid and the intermediate yoi have been using in Problem 3 in the biosynthesis of the piperidine alkaloid are both electrophilic at position 2. You also need an intermediate derived from nicotinic acid which is nucleophilic at position 3. The biosynthesis involves reduction.)... 

Nicotine and related pyridine alkaloids (A) Ammodendrine (A) anabasine (A) arborine (AA) boldine and other aporphine alkaloids (AA) berberine and related protoberberine alkaloids C-toxiferine (AA) coniine and related piperidine alkaloids (A) cytisine, lupanine, and other quinolizidine alkaloids (A) tubocurarine (AA) codeine (A) erysodine and related Erythrina alkaloids (AA) histrionicotoxin (AA) lobeline (A) methyllycaconitine (AA) pseudopelletierine (A)... 

There are three principal groups of alkaloids derived from ornithine nicotine, the pyrrolizidines, and the tropanes, all having significant biological effects. From lysine are derived the piperidine alkaloids... 

Epibatidine, a piperidine alkaloid isolated from the frog, Epidedobates tricolor, and similar in structure to nicotine was found to be a potent analgetic (about 200x more potent than morphine) but was found to possess a non-opioid mechanism of action. Subsequent studies... 

Coniine (piperidine alkaloid), N-methyl coniine, conhydrine, /l-coniceine, and pseudconhydrine are the toxins identified. Coniine has a number of pharmacological activities resembling nicotine. It is capable of producing stimulation followed by depression of autonomic ganglia. 

Piperidine alkaloid toxins, such as coniine, are structurally similar to nicotine, and contained in all parts of the plant. 

The technique of chemical ionisation mass spectrometry has shown promise in the structural elucidation of nicotine alkaloids. The absolute configurations of a number of simple piperidine alkaloids have been determined by o.r.d. and... 

Lobelia tupa Known in Chile as tupa or tabaco deldiablo, Mapuche Indians have been reported to smoke the leaves of this plant as an inebriant (Duke 1985 Schultes Hofmann 1980). Piperidine alkaloids not known to be psychoactive are found in this plant, although lobeline is said to exert a nicotine-like activity. Lobelia inflata was used ceremonially by North American Crow Indians, and in love magic by Mesquakie and Pawnee Indians (IGndscher 1992). 

There is an alternative way of viewing the above results, however. It could be that the biosynthetic pathway to the pyrrolidine ring of nicotine is similar (in part) to the route to the piperidine alkaloids. Part of the model suggested for the biosynthesis of the piperidine nucleus from lysine (see above) could be easily adapted to account for the C02 and nornicotine results, that is variable/in-complete equilibration of bound putrescine (arising by enzyme-mediated decarboxylation of ornithine) with unbound material. L-Ornithine decarboxylase (EC 4.1.1.17, L-ornithine carboxy-lyase) occurs widely in higher plants and like L-lysine decarboxylase requires pyridoxal phosphate as a co-factor. ... 

There are some difficulties associated with a highly attractive model for piperidine alkaloid biosynthesis (this Report, p. 9). There is still debate about the symmetrical or unsymmetrical incorporation of into nicotine (this... 

Most remarkable for proving that structural relationships are not always what they seem are anatabine [(34) p. 11] and dioscorine (8). Inspection and experience with other piperidine alkaloids leads one to expect a biosynthesis for the piperidine ring [heavy bonding in (8)] from lysine via A -piperideine (3). However, in both cases it turns out that this ring derives from nicotinic acid [the exceptional derivation of the piperidine nuclei of coniine and pinidine (9) from acetate has been known for some time ]. 

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). 

Alkaloids that possess an aromatic pyridine ring often are called pyridine alkaloids (Leete, 1980 Pinder, 1993 Strunz and Findlay, 1985) approximately 250 alkaloids of this type are known (Verpoorte et al., 1991). Although many are derived from nicotinic acid (Fig. 28.18), others arise from aro-matization of piperidine alkaloids and other pathways (Waller and Nowacki, 1978). This chapter includes several of the most important compounds of this type, although others (such as a number of monoterpene-derived alkaloids, Nu-phar alkaloids, and sesquiterpene alkaloids of the Celastra-ceae) are discussed in Chapter 36. 

L. inflata L. is a traditional medicinal plant native to North America. It contains several piperidine alkaloids. The main alkaloid is lobeline which has a stimulatory effect on the respiratory center and it is applied in the cases of asthma, gas- and narcotic-poisoning. Thus, lobeiine is currently the subject of renewed interest for the treatment of drug abuse and neurological disorders, like Alzheimer s or Parkinson s disease, which pose an important public health problem in industrial countries. As lobeiine can act as a competitive nicotinic receptor antagonist, it is frequently used in antismoking preparations. Interest in Lobelia alkaloids, and in particular (-)-lobeline, the most active of them, has increased in recent years due to their activity on the central nervous system (CNS). 

The four main alkaloids are coniine, y-coniceine, iV-methylconiine, and conhydrine. Conhydrine occurs in the smallest proportions and has the weakest pharmacological action [3,4,19,20, 31,67, 85, 87]. The most distinctive action of the three other hemlock alkaloids plus nicotine is their ability, provided the dose is small, to inhibit the crossed extensor reflex and the so-called knee-jerk by an action potential in the spinal cord. Since neurons in the spinal cord may both be inhibited and activated by the action of hemlock, the mechanisms involved are a bit complicated. If the alkaloids initially stimulate inhibitory neurons rather than blocking excitatory ones, the antagonistic relationship of the two substances may be explained. There is evidence that its central synapse is controlled by polysynaptic inhibitory pathways, although the patellar reflex is monosynaptic [3, 19, 67]. It is possible that the C. maculatum piperidine alkaloids may act upon the mechanism that regulates the amniotic liquid, adding to the production of malformations. Finally, lack of fetal movement, whatever its origin, can also cause limb malformations. 

Green BT, Lee ST, Panter KE, Welch KD, Cook D, Pfister JA, Kem WR (2010) Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors. Neurotoxicol Teratol... 

Nicotinoids with Basic Pyrrolidine or Piperidine Moiety. Nicotinoids are (i) congeners of nicotine, usually minor alkaloids but the term also includes (ii) the principal tobacco alkaloid, nicotine itself. From the structural point of view the nicotinoids may be divided into five groups (Figs. 3.8 and 3.9) ... 

Simple examples of piperidine alkaloids are iV-methylpelletierine 6.19) and the hemlock alkaloid, coniine 6.14). In these bases the structural relationship is manifestly close. This relationship is similarly apparent between anabasine 6.20) and anatabine 6.7) which are, moreover, found in the same plant. It is however, clear, from biosynthetic experiments, that whilst the piperidine rings of iV-methylpelletierine 6.19) and anabasine 6.20) derive from the amino acid lysine 6.17) those of coniine 6.14) and, most surprisingly, anatabine 6.7) have quite different origins. It is proved that anatabine 6.7) is formed from two molecules of nicotinic acid 6.4) [4] (the labelling results, and a suggested pathway, is illustrated in Scheme 6.4). Only the pyridine ring of anabasine derives from... 

Nicotine boldine and other aporphine alkaloids C-toxiferine coniine and other piperidine alkaloids cytisine and other quinohzidine alkaloids epibatidine tubocurarine Berbamine, berberine, and other isoquinoline alkaloids cinchonidine and other quinoline alkaloids corynanthine, yohimbine, and other indole alkaloids emetine ephedrine ergometiine and related ergot alkaloids Ergocornine and related ergot alkaloids bulbocapnine and related aporphine alkaloids anisocycline, stylopine, and related protoberberine alkaloids salsolinol and related isoquinohnes BicuculUne, cryptopine, hydrastine, and related isoquinoline alkaloids securinine harmaline and related beta-carboline alkaloids Corymine, strychnine, and related indole alkaloids Histrionicotoxin and related piperidines ibogaine and related indole alkaloids nuciferine and related aporphine alkaloids... 

Pyridine alkaloids are compounds with a pyridine nucleus and a pyrrohdine or piperidine unit. The pyrrohdine ring appears in nicotine and the piperidine ring in anahasine. Typical alkaloids from this group are nomicotine and anatahine. The a of pyridine alkaloids is nicotinic acid, the j8 is dihydronicohnic acid, the q> is 1,2-dihydropyridine (Figure 61). The A is nicotine and its P is nomicotine. ... 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Alkaloids, e.g. pipeline, coniine, trigonelline, pilocarpine, nicotine and sparteine, possess a pyridine or modified pyridine heterocyclic ring system (e.g. piperidine ring). 

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