Piperidine alkaloids lobeline

Sophora species [Leguminosae]) and the piperidine alkaloid lobeline (37) (from Lobelia inflata L. [Campanulaceae]), which have high affinity for 4p2 nAChRs lobeline also improves learning and is anxiolytic in vivo [137, 150, 151] (Scheme 42.9). Cytisine and derivatives may also be of therapeutic interest for PD (see Sect. 4). Huperzine A and tacrine hybrid structures (huprines) are also under investigation as nAChR agonists for AD, in addition to their documented ChE inhibitory and Mi mAChR agonistic properties [10] (see Sect. 2.2). 

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. 

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)... 

In contrast to the biosynthesis of many other piperidine alkaloids, the incorporation of [2- C]lysine into lobeline (13) was found to be symmetrical, i.e. C-2 and C-6 were equally labelled. Symmetrization of the label could occur on formation of lobelanine (12), a known late precursor, or at a possible earlier intermediate,... 

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). 

Piperidine alkaloids occur in only a few species of higher plants. However, (S)-pipecolic acid 3 [121] is widely distributed in higher plants, microorganisms and animals. Lobeline 4 is the main constituent of lobelia alkaloids (Lobelia inflata, Campanulaceae). It is a respiratory stimulant in mammals. Pi-perine 5 is the active ingredient in black pepper (Piper nigrum). On hydrolysis it furnishes piperic acid 6 and piperidine (hence its name) [122] ... 

L-lysine Piperidine alkaloids Piperidine Anaferine Lobelanine Lobeline N-methylpelletierine Pelletierine Piperidine Piperine Pseudopelletierine Sedamine... 

Pelletierine is biosynthesized through the incorporation of lysine. Among the several types of alkaloid possessing the piperidine nucleus, lobeline involves a similar biosynthetic pathway (Section 4.4) as that of pelletierine, whereas arecoline and coniine are biosynthesized through completely different pathways. The former alkaloid is derived lirom nicotinic acid (Section 10.3), and the latter alkaloid is biosynthesized via the polyketide pathway (Section 15.1). 

Biological activities biosynthesis of piperidine alkaloids HPLC and LC-MS/MS Lobelia inflata lobeline and their derivates pelletierine Piper nigrum piperine Punic a granatum... 

While for developing of simple piperidine alkaloids, e.g., pelletierine (Punica granatum), piperine (Piper nigrum et longum), and lobeline (Lobelia inflata), only one molecule of lysine is necessary, for quinolizidine alkaloids - e.g., lupinine (Lupinus luteus), sparteine of antiarrhythmic activity (Sarothamnus scoparius), and cytisine of respiratory stimulant effect (Laburnum species) - two molecules of lysines are indispensable. It was also proved that lycopodine (Lycopodium tristachyum, clubmoss) of quinolizidine structure has no polyketide origin, but it is a modified dimer of pelletierine, which, in turn, is derivable from lysine and acetate. 

Eor direct characterization of disubstituted piperidine alkaloids in extracts of L. inflata, tandem mass spectrometric method was developed using electrospray ionization. Analysis was performed in positive ion mode on a triple quadropole LC/MS system. The identification and structural elucidation of the alkaloids were performed by comparing their changes in molecular mass (AM), full-scan MS-MS spectra with those of lobeline, lobelanine, norlobelanine, and lobelanidine. These alkaloids and ten other derivatives were identified in the plant extracts. 

Summarizing, the HPLC-DAD method of Kursinszki et al. [40] is reliable, simple, and sensitive. It can be used for determination of lobeUne in the extracts of L. inflata. LC-MS-MS quadropole with electrospray ionization method was very suitable for the identification of lobeline and related piperidine alkaloids in L. inflata. 

For identification of alkaloids of plant obtained by vegetative micro propagation, the LC-MS/MS quadropole with electrospray ionization method was very suitable. In plant cultivated on field, 52 alkaloids (lobeline and related piperidine alkaloids) were found and identified. Of them, as main component, was identified the 8-ethyl-lO-phenyl-lobelienonol isomer of molecular ion [M + H]" of miz 288 (Fig. 11.29), [52]. 

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). 

Recently, numerous publications were presented which were interested in the multidrug-resistant activity of piperidine like lobeline, pipeline [60, 61], and other alkaloids, e.g., cinchonine and acridone [62, 63]. 

In Lobelia inflata, two types of piperidine alkaloids were detected alkaloids of phenolic side chaines, as lobeline, lobelanine, norlobelanine, sedamine, and the dimer lobinaline further, alkaloids of aliphatic side chains diethyllobelidiol and methyl-ethyllobelidiol. It is important to mention that lobelane and nor-lobelane as... 

Kursinszki L, Ludanyi K, Szoke E (2008) LC-DAD and LC-MS-MS analysis of piperidine alkaloids of Lobelia inflata L. (in vitro and in vivo). Chromatographia 68 27-33 Balvanyos I, Kursinszki L, Szoke E (2001) The effect of growth regulators on the biomass formation and lobeline production of Lobelia inflata L. hairy root cultures. Plant Growth Regul 34 339-345... 

Ma Y, Wink M (2008) Lobeline, a piperidine alkaloid from Lobelia can reverse P-gp depentent multidmg resistance in tumor cells. Phytomedicme 15(9) 754-758... 

Contains about 0.48% pyridine (piperidine) alkaloids composed mainly of lobeline, with lesser amounts of lobelanine and lobelanidine. Other alkaloids present include norlobelanine (isolobelanine), lelobanidine, norlelobanidine, norlobelanidine, lobinine, isolobinine, lobina-nidine, isolobinanidine, 8-methyl-10-ethyllo-belidiol, and 8-methyl-10-phenyllobelidiol, among others. ... 

Alkaloids with the piperidine nucleus, such as pelletierine (Punica grana-tum), lobelanine Lobelia inflata) and piperine Piper nigrum), have a typical biosynthesis pathway. It starts with L-lysine and continues via cadaverine (biogenic amine), A -piperideine and A -piperidinium cations and lobelanine, to be synthesized as lobeline. Piperine is synthesized from A -piperideine via piperidine (Figure 49). For the transformation from A -piperideine to A -piperideine cation, the residue from acetyl-CoA is needed, together with SAM activity in the transformation to lobelanine. Piperine is synthesized from piperidine through the formation of amide. 

Meperidine (isonipecaine, Demerol , and Dolantin ) is the methyl ester of methyl-4-phenylpi-peridine-4 carboxylic acid. It is used in the form of its soluble hydrochloride. The piperidine nucleus is also present in many alkaloids, such as atropine or lobeline, which are not analgesics, as well as in morphine. 

In each of the alkaloids discussed so far, lysine has been found to be incorporated into the piperidine ring without the intervention of a symmetrical intermediate. However, examples have been discovered recently where lysine is incorporated symmetrically, e.g. cernuine,59 decodine (97),60 and now lobeline (96).61 It is possible, though not yet proven, that cadaverine is an intermediate in the biosynthesis of these alkaloids. 

The pattern of incorporation is in marked contrast with that observed for the closely related alkaloid sedamine (see Scheme 15). However, there is a potentially symmetrical intermediate (95, Scheme 19) in the late stages of the proposed pathway to lobeline so that lysine may still be incorporated non-symmetrically into the early piperidine intermediate (94) by one of the two paths in Scheme 16. 

Thebaine, the methoxy derivative of morphine, is also a habit-forming substance, but its primary toxic effects are similar to those of strychnine, a convulsant poison, rather than narcosis. Also, there are alkaloids having different structures but similar toxic actions. Lobeline, a lobelia alkaloid, which has a piperidine nucleus, shows pharmacologic action similar (but less potent) to that of nicotine, a tobacco alkaloid that has a pyridine-pyrrolidine ring system. The structure, occurrence, physical properties, and toxicity of some important alkaloids are presented in the following sections. 

L. inflata (Indian tobacco) is indigenous to the Eastern and Central states of USA and Canada. The plant contains ca. 0.3% of alkaloids. The L. a. are 2,6-di-substituted piperidine derivatives. Among the ca. 20 L. a., lobeline is the major alkaloid. When administered parenterally (3-10 mg) lobeline stimulates respiration and was used in the past as a respiratory analeptic agent for asthma, collapse, and narcosis incidents. When taken orally it is rapidly degraded and thus not effective. Since lobeline potentiates the action of nicotine and induces nausea and revulsion it has been developed clinically in depot form in antismoking preparations. - The piperidine ring is biogenetically derived from lysine and the substituents from phenylalanine. 

L-Lysine is a basic amino acid with six C-atoms. The secondary products derived from L-lysine often are piperidine or pyridine derivatives (cf. the formulas of dipicolinic acid, desmosine, pipecolinic acid, lobeline, etc.). Also quinolizidines, e.g., the alkaloids lupinine and sparteine, are synthesized from L-lysine. 

The Lobelia alkaloids were first detected by Procter in 1850. At the begiiming of the twentieth century, Wieland and Scheuing isolated the first alkaloids from L. inflata. The most important alkaloid of the family Lobeliaceae is lobeline, which is an a, ai-disubstituted piperidine. Further, other alkaloids of L. inflata have been isolated, with their structures described [29, 34, 35]. 

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