Nicotine alkaloids sites

Lobelia or Indian tobacco consists of the dried leaves and tops of Lobelia inflata (Campanulaceae), an annual herb from the USA and Canada. Lobelia contains about 0.2-0.4% of alkaloids, of which the piperidine derivative lobeline (Figure 6.23) is the chief constituent. Minor alkaloids identified include closely related structures, e.g. lobelanine (Figure 6.23). The North American Indians employed lobelia as an alternative or substitute for tobacco (Nicotiana tabacum Solanaceae), and it is found that lobeline stimulates nicotinic receptor sites in a similar way to nicotine, but with a weaker effect. Lobeline has been employed in preparations intended as smoking deterrents. The crude plant drug has also long been used to relieve asthma and bronchitis, though in large doses it can be quite toxic. 

Galantamine, unlike the other anticholinesterases in clinical use, is derived from the alkaloids from the daffodil and snowdrop family. It is a reversible, competitive inhibitor of acetylcholinesterase with some inhibitory action on butyryl cholinesterase. It is also an agonist at nicotinic receptor sites. Although a clinically effective drug, galantamine frequently causes gastrointestinal side effects. 

Tropane alkaloids are compounds known as muscarinic receptor antagonists. Atropine, its best-known member, and a number of other compounds, block the action of the neurotransmitter acetylcholine on post-ganglionic cholinergic nerves of the parasympathetic nervous system, essentially by blocking its binding to muscarinic cholinergic receptors, whereas they are much less potent at nicotinic receptor sites. 

At a low concentration, the tobacco alkaloid nicotine acts as a ganglionic stimulant by causing a partial depolarization via activation of ganglionic cholinocep-tors (p. 108). A similar action is evident at diverse other neural sites, considered below in more detail. 

The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline Figure 7-3) are well absorbed from most sites of administration. Nicotine, a liquid, is sufficiently lipid-soluble to be absorbed across the skin. Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines but is nevertheless toxic when ingested—eg, in certain mushrooms—and it even enters the brain. Lobeline is a plant derivative similar to nicotine. These amines are excreted chiefly by the kidneys. Acidification of the urine accelerates clearance of the tertiary amines. 

Nicotine biosynthesis is localized in the roots of Nicotiana plants, and the alkaloids are transported to the shoots in the xylem stream,70 mainly to young leaves and stems and the reproductive parts of the plant.72 At first glance, the costly transport mechanisms seem to be a disadvantage, as there is a time lag of 10 hr from time of induction until the increase of nicotine production.73 The roots, however, as the site of synthesis are well protected against herbivory and continue the production, even when up to 88% of the total leave area is removed.74 Optimization of the cost-value ratio seems to be the reason for the inducible defense acting as a cost-saving... 

As can be seen from Table I a substantial number of alkaloids display significant insect toxicity, including nicotine, pipeline, lupine alkaloids, caffeine, gramine, strychnine, berberine, ephedrine, and steroidal alkaloids. Only the specialists can tolerate the respective alkaloids. The tobacco homworm (Manduca sexto), for example, can grow on a diet with more than 1% nicotine without any adverse effects. Most of the nicotine is either degraded or directly eliminated via the Malpighian tubules and in feces 182). Because nicotine binds to the acetylcholine (ACH) receptor, it is likely that in Manduca this receptor has been modified in such a way that ACH can still bind, but not nicotine (so-called target site modification). 

As a rule of thumb, we can assume that all parts of an alkaloidal plant contain alkaloids, although the site of synthesis is often restricted to a particular organ, such as the roots or leaves. Translocation via the phloem, xylem, or apoplastically must have therefore occurred. Phloem transport has been demonstrated for quinolizidine, pyrrolizidine, and indolizidine alkaloids, and xylem transport for nicotine and tropane alkaloids 36,39,511). 

Ant venoms from the genus Solenopsis have provided an array of 2,6-disubstituted piperidines, including 197-206. A review of the fungicidal, insecticidal and repellent activity of these alkaloids has appeared [476]. Both solenopsin A (198a) and isosolenopsin A (200) were potent inhibitors (Ki = 0.16 pM and 0.24 pM, respectively) of [ HJ-perhydrohistrionicotoxin binding to sites associated with the nicotinic receptor-gated ion channel in the Torpedo califomica electric organ [477]. 

It is now generally recognized that the most intensively studied alkaloids (nicotine in tobacco hyoscyamine in Datura, Atropa, and Hyoscyamus) are produced in quantity in the roots of intact plants, though other sites of formation are not entirely excluded. A fully developed tobacco leaf does not elaborate nicotine, but it has not yet been proved that this almost cosmopolitan alkaloid is produced only in the roots in all other plants. 

A classic example of a ligand-gated ion channel from the cys-loop superfamily is the nAChR. The nicotinic AChRs are named so because they can be activated by the tobacco alkaloid nicotine in the same way they are activated by ACh. It should be mentioned that the muscarinic A.ChR s, which respond to the alkaloid muscarine, are not ion channels, and therefore not discussed in this chapter. The nAChR is made up of five subunits (al, pi, 7, 5, and e) with two binding sites for ACh (Figures 16.6B and 16.9). The nAChRs are expressed in nerves and skeletal muscle (but not smooth muscle) and play an important role in the fast synaptic transmission in synaptic neuronal-neuronal and neuromuscular junctions. nAChR is a nonselective cation channel that allows the flow of many cations, but not anions. After ACh binds to the nAChR it allows Na" " and also Ca " ", to flow down their electrochemical gradient into the cell, which depolarizes the cell membrane and generates an action potential (Figure 16.6B). 

The nicotinic acetylcholine (ACh) receptor mediates neurotransmission postsynaptically at the neuromuscular junction and peripheral autonomic ganglia in the central nervous system (CNS), it largely controls release of neurotransmitters from presynaptic sites. The receptor is called the nicotinic acetylcholine receptor because it is stimulated by both the neurotransmitter ACh and the alkaloid nicotine. 

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