Hyoscyamine tropane alkaloids

It has been confirmed that isoleucine but not 3-hydroxy-2-methylbutanoic acid is a precursor for the tiglic acid which is the esterifying acid in some tropane alkaloids [e.g., meteloidine (77) (735)]. In the biosynthesis of meteloidine (77) from 3a-hydroxytropane (1), the hydroxyl groups at C-6 and C-7 are most probably introduced after esterification at C-3 (5) (Scheme 23). In this connection we would point out that scopolamine (89) is a well-known 2,3) metabolite of hyoscyamine (27) and that the reaction proceeds via 6-hydroxyhyoscyamine [(—)-anisodamine (63)] and 6,7-dehydrohyoscyamine (211) (Scheme 26). 

The family Solanaceae consists of about 85 genera and 2800 species of plants, of which, 80 are of medicinal value in the Asia-Pacific region. Solanaceaeare well known for their parasympatholytic tropane alkaloids, such as hyoscyamine. Classic examples are Atropa belladonna L. (belladona herb, British Pharmacopoeia 1963), Datura stramonium L. (stramonium, British Pharmacopoeia, 1963), and the dried leaves and flowering tops of Hyoscyamus... 

The cholinergic hallucinogens all have common chemical constituents that are responsible for their pharmacological effects (Robbers et al. 1996). These are the tropane alkaloids hyoscyamine, scopolamine (or hyoscine), and atropine (figure 9.16). It is scopolamine, and not atropine or hyoscyamine, which primarily produces the central and hallucinogenic effects because it is the only one that passes the blood-brain barrier sufficiently. However, all three have peripheral effects. Datura stramonium contains 0.1-0.65% tropane alkaloids, which is principally... 

The tropane alkaloids (—)-hyoscyamine and (—)-hyoscine are found in the toxic plants deadly nightshade (Atropa belladonna) and thornapple (Datura stramonium) and are widely used in medicine. Hyoscyamine, usually in the form of its racemate atropine, is used to dilate the pupil of the eye, and hyoscine is employed to control motion sickness. Both alkaloids are esters of (—)-tropic acid. 

The Mannich reaction was used for the first synthesis of tropine, the parent alcohol of the tropane alkaloids. One of the natural tropane alkaloids used medicinally is hyoscyamine, sometimes in its racemic form atropine. Hyoscyamine is an anticholinergic, competing with acetylcholine for the muscarinic site of the parasympathetic nervous system, and thus prevendng the passage of nerve impulses. 

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

A. Alkaloids 1. Belladonna-type solanaceous tropane alkaloids [Atropine (1), (—)-Hyoscyamine (2), Scopolamine ((—)-Hysoscine)(3)] Atropa belladonna L. (belladonna), Datura metel L., D. stramonium L. (jimson weed), Hyoscyamus niger L. (henbane), Mandragora officinarum L. (European mandrake), and other solanaceous species Anticholinergics (parasympatholytics)... 

Certain plants of the family Solanaceae, such as Atropa belladonna L., Hyoscyamus niger L., and Datura stramonium L., have been used medicinally for centuries in Europe because they contain tropane-type alkaloids.For example, atropine (1) [a racemic mixture of (+)- and (—)-hyoscyamine (2)] and (-)-hyoscyamine are competitive antagonists at the muscarinic acetylcholine receptor site, leading to antispasmodic and antiallergic effects. Scopolamine [(—)-hyoscine)] (3) is used in a transdermal patch for the prevention of motion sickness. Since these tropane alkaloids penetrate the blood-brain barrier, they also have psychoactive effects. ... 

Tropane alkaloids Tropane Atropine Cocaine Hyoscyamine Scopolamine/ hyoscine... 

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

Tropane alkaloids have a tropane (C4N skeleton -f) nucleus. Structurally, these alkaloids synthesize as postcursors of pyrrolines (Figure 57). a, /3,

tropane alkaloids (e.g., atropine, hyoscyamine, cocaine, tropinone, tropine, littorine and cuscohy-grine) have a strong biological activity, especially as neurotransmitters. 

Tropane alkaloids Hyoscyamine 6/3-hydroxylase Hyoscyamus niger Atropa belladonna... 

N.A. Tropane alkaloids (hyoscyamine, hyoscine), flavonoids, withanolides, coumarins, tannins.100 Treat asthma, coughs, fevers, skin conditions. 

The tropane alkaloids (—)-hyoscyamine and (—)-hyoscine are among the most important of the natural alkaloids used in medicine. They are found in a variety of solanaceous plants, including Atropa belladonna (deadly nightshade), Datura stramonium (thornapple) and other Datura species, Hyoscyamus niger (henbane), and Duboisia species. These alkaloids... 

Tropane alkaloids, principally hyoscyamine and hyoscine, are also found in two other medicinal plants, scopolia and mandrake, but these plants find little current use. Scopolia (Scopolia carniolica Solanaceae) resembles belladonna in appearance, though it is considerably smaller. Both root and leaf materials have been employed medicinally. The European mandrake (Mandragora officinarum Solanaceae) has a complex history as a hypnotic, a general panacea, and an aphrodisiac. Its collection has been surrounded by much folklore and superstition, in that pulling it from the ground was said to drive its collector mad due to the unearthly shrieks emitted. The roots are frequently forked and are loosely likened to a man or woman. Despite the Doctrine of Signatures, which teaches that the appearance of an object indicates its special properties, from a pharmacological point of view, this plant would be much more efficient as a pain-reliever than as an aphrodisiac. 

Tropane Alkaloids.—It is known that tropine (26) is a precursor for meteloidine (27),42 and its close relative hyoscyamine (29) is a precursor for scopolamine (28).43 Experiments with samples of (26) labelled with /3-tritium at C-6 and C-7 show that entry of the two /S-hydroxy-groups in (27) must occur with normal retention of configuration since almost complete loss of tritium occurred.44 Tritium was again lost almost completely on formation of scopolamine (28). On the assumption that early conclusions45 on the sequential intermediacy of (30) and (31) in the biosynthesis of (28) are correct, formation of (30) involves normal retention of configuration (loss of half the tritium) and cis-dehydration then occurs to give (31) (loss of remaining tritium). [In these experiments the hyoscyamine (29) isolated showed appropriately no loss of tritium.]44... 

HASHIMOTO, T., HAYASHI, A., AMANO, Y, KOHNO, J., IWANARI, H., USUDA, S., YAMADA, Y., Hyoscyamine 6P-hydroxylase, an enzyme involved in tropane alkaloid biosynthesis, is localized at the pericycle of the root. J. Biol. Chem., 1991,266, 4648-4653. 

Hyoscyamine, scopolamine, and other tropane alkaloids (AA) acetylheliosupine and some other pyrrolizidine alkaloids arecoline (A) berbamine, berberine, and other isoquinoline alkaloids dicentrine and other aporphine alkaloids strychnine, brucine cryptolepine (AA) sparteine and other quinolizidine alkaloids (A) pilocarpine (A) emetine himbacine and other piperidine alkaloids (A) imperialine (AA) muscarine (A)... 

The usefulness of GC-MS analysis for biosynthetic studies was demonstrated by Patterson and O Hagan [74] in their investigation of the conversion of littorine to hyoscyamine after feeding transformed root cultures of Datura stramonium with deuterium-labeled phenyllactic adds. This study complements previous investigations on the biosynthesis of the tropate ester moiety of hyoscyamine and scopolamine [75], where GC-MS played a key role. It also has general relevance in the biosynthetic pathway of tropane alkaloids in the entire plant kingdom [76]. 

Tropane alkaloids are an important class of natural products possessing different and interesting pharmacological activities. Hyoscyamine (atropine in the racemate form), scopolamine, and cocaine are the major representatives of this class. They are commonly found in plant materials, mainly in genera belonging to three families Solanaceae, Erythroxylaceae, and Convolvulaceae. The importance of these compounds requires that there are accurate analytical methods for their determination in plants and in biological matrices. This chapter describes the state-of-the-art of analytical procedures (extraction and analysis) for analyzing tropane alkaloids. 

As in Nicotiana, it was debatable whether ADC or ODC might provide the putrescine incorporated. This possibility was tested by growing roots in the presence of DFMO and DFMA (Robins and Walton, 1993) in experiments analogous to those performed in Nicotiana. Inhibition of ADC specifically depressed hyoscyamine accumulation and the pools of intermediates, indicating that ADC might be more important for the tropane alkaloid pathway. 

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