Hyoscyamine, Atropine, Tropine

In their physiological action atropine and hyoscyamine are similar and exert what is termed a mydriatic action causing dilation of the pupil of the eye. This action may be produced eithef by external application or by taking internally. As little as i part atropine in 130,000 parts of water will exert a distinct action on the eye. They decrease body secretions and also affect the heart. Taken internally they are poisonous in as little as o.i gm. Tropine exerts no mydriatic action when applied to the eye but in large doses internally it does produce dilation. In addition to the use of these alkaloids in the pure form, extracts of belladonna are also used. 

Belonging to the same chemical group as atropine is the important alkaloid cocaine, C17H21O4N. It is obtained from the leaves of the coca plant, Erythroxylon coca, which grows in South America (Bolivia and Peru) and in Java and Ceylon. Distinction should be made between the coca plant and the cacao bean from which cocoa and chocolate are made. 

Cocaine like atropine and hyoscyamine hydrolyzes into a simpler nitrogen base and other products. The base is known as ecgonine and the other products obtained are methyl alcohol and benzoic acid. The hydrolysis proceeds in two steps as follows  

This hydrolysis indicates that the simpler base ecgonine is both an alcohol and an acid and that cocaine is the double ester of this base with benzoic acid and methyl alcohol. Ecgonine bears the same relation to cocaine that tropine does to atropine. In its reaction ecgonine proves to be very similar to tropine and as indicated by its composition formula it differs simply by CO2. 

This indicates that ecgonine is the mono-carboxyl derivative of tropine and according to Willstater s formula for tropine ecgonine is as follows  

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DI-HETERO-CYCLIC ALKALOIDS Hyoscyamine, Atropine, Tropine... 

The alkaloids of this group are derived from a combination of a piperidine and a pyrrolidine ring, designated as tropane (Figure 14.2). The 3-hydroxy derivative of tropane is known as tropine and is the basic component of atropine. When atropine is hydrolyzed, it forms tropine and tropic acid (a-phenyl-p-hydroxy-propionic acid). Atropine is the tropic acid ester of tropine. It has been prepared synthetically. Tropic acid contains an asymmetric carbon atom. The racemic compound (atropine) as obtained naturally or as synthesized may be resolved into its optically active components, d- and /-hyoscyamine. Atropine is racemic hyoscyamine that is, it consists of equal parts of /-hyscyamine and plant cells and also in the process of extraction, so that the relative proportion of the isomers in the plants and in the preparations varies. However, atropine itself does exist in small amounts in the plants, although most of it is formed from the /-hyoscyamine in the process of extraction. 

The ease with which Z-hyoscyamine is racemized by alkali would suggest (235) that atropine is the intermediate in the hydrolysis of Z-hyoscyamine to tropine and dZ-tropic acid. If Z-hyoscyamine is hydrolyzed in water (60) tropine and Z-tropic acid are formed. From this it would appear that the optical activity of this Zeworotatory alkaloid may be attributed to the asymmetry of the tropic acid residue or that racemization of the tropine during hydrolysis has occurred. This last assumption apparently is not valid for all attempts to resolve tropine have failed (205). 

Structure occurrence The T. a. occur principally in plants of the Solanaceae, Convolvulaceae, Eryth-roxylaceae, Proteaceae, and Rhizophoraceae families as well as in isolated species of the Euphorbiaceae and Brassicaceae. The most important of the ca. 140 known T. a. are either esters of 3a-tropanol (tropine) or, less commonly, of 3/S-tropanol (pseudotropine). Prominent examples are the T. a. of the Solanaceae hyoscya-mine [racemate ( )-hyoscyamine= atropine], scopolamine, and the T. a. of the Erythroxylaceae (Coca... 

Tropane Tropine Tropine, hyoscyamine, atropine, scopolamine Paraspasmolytic... 

The phannacokinetics of S- and / -enantiomers of hyoscyamine in humans have been examined by LC-ESI-MS/MS [13]. Plasma supplemented with atropine was incubated with human serum (not containing atropinesterase (AtrE)) and with rabbit serum possessing AtrE (EC 3.1.1.10), which stereospecificaUy hydrolyzes 5-hyoscyamine into tropine and tropic acid while leaving / -hyoscyamine unaffected. The estimation of the differences between the total hyoscyamine content in the aliquots incubated with human and rabbit sera allowed the determination of the remaining / -hyoscyamine and hydrolyzed S-hyoscyamine. Both enantiomers were detected in the MRM mode. The method proved to be reproducible, precise (RSD 2-9 %), accurate (93-101 %), and selective. The enantioselective assay was applied to the analysis of atropine degradation in rabbit semm in vitro as well as to human in vivo plasma samples from a pesticide-poisoned patient treated with atropine. The method was also applied for kinetic studies of atropine administered to swine, where no obvious stereoselective elimination was found [82]. 

When heated with acids or alkalis, hyoscyamine undergoes hydrolysis into tropine and dZ-tropic acid probably via conversion into atropine, and it is this alkaloid which is hydrolysed. According to Gadamer, when hyoscyamine is hydrolysed with cold water the products are inactive tropine and Z-tropie acid. Amenomiya has shown that Ladenburg and Hundt s partially synthetic d- and Z-atropines were probably mixtures of atropine with d- and Z-hyoscyamines. He resolved dZ-tropic acid into the d- and Z- forms, esterified these with tropine in 5 per cent, hydrochloric acid, and so obtained d- and Z-hyoscyamines, the latter identical with the natural alkaloid, d- and Z-Hyoscyamines have also been obtained by Barroweliff and Tutin by the resolution of atropine by means of d-camphorsulphonic acid. 

This synthetic tropidine was converted into bromodihydrotropidine by hydrogen bromide in aeetie aeid, and the solution heated with 10 per cent, sulphurie acid at 200-10°, when it passed into -tropine,and, sinee this may be partially converted into tropine by oxidation to tropinone and reduction of the latter by zinc dust and hydriodic acid, this series of reactions affords a complete synthesis of tropine and of the tropeines. Combining the formula given above for tropine with that of tropic acid, atropine and hyoscyamine are represented as follows ... 

Hyoscine (Scopolamine, Atroscine), Ci,H2i04N. The name hyoscine was first used by Hohn and Reichardt for the basie hydrolytic product of hyoscyamine, now known as tropine. It was subsequently used by Ladenburg for a supposed isomeridc of atropine, Cj HjgOjN, isolated from the mother liquors of hyoscyamine. This was found by Schmidt, Hesse and others to be identical with scopolamine, Ci,H2i04N, obtained by Schmidt from Scopolia japonica. The name hyoscine has priority and is in use, but scopolamine is also employed, especially in Germany. 

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. 

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 is formed when pyrrolidine and piperidine are condensed. Closely related to tropane are tropine, the principal nucleus of the solanaceous alkaloids, atropine, hyoscyamine, hyoscine, and belladonnine, and ecgonine, the nucleus of cocaine (Figure 11.7). 

Hyoscyamine (duboisine) and the racemate atropine are mACh-R antagonists and a number of atropine derivatives also have this property, namely anisodamine (6P-hydroxyhyoscyamine), 7 (3-hydroxyhyoscyamine, hyoscine (6,7-epoxyhyoscyamine or scopolamine), benzoyltropein (tropine benzoate), littorine (tropine a-hydroxyphenylpropionate), tigloidine (pseudotropane tiglate) and tropacocaine (pseudotropine benzoate). The further derivatives apoatropine (a-dehydrohyoscyamine) and tropine are very toxic. 

SYNS ATROPIN (GERMAN) EYEULES dl-HYOSCYAMINE 2-PHENYLHYDRACRYLIC ACID-3-a-TROPANYL ESTER P-PHENYL-y-OXYPROPION-SAEURE-TROPYL-ESTER (GERNLAN) l-0-H,5-a-H-TROPAN-3-a-OL ( )-TROPATE (ESTER) dl-TROPAN-YL-2-HYDROXY-1-PHENYLPROPIONATE TROPIC ACID, ESTER with TROPINE TROPIC ACID-3-a-TROPANYL ESTER TROPINE TROPATE dl-TROPYLTROPATE ( )-TROPYL TROPATE... 

Hyoscyamine and atropine are therefore tropic acid esters of the base tropine. The constitution of tropine according to Willstater is as follows ... 

Tropine is a simpler base than the other alkaloids and is not found as such in the plants but is obtained by hydrolyzing not only atropine and hyoscyamine but other solanacese alkaloids as well. It is crystalline, m.p. 63°, and is soluble in water, alcohol, ether or benzene. As shown in its formula it is an alcohol yielding esters with tropic acid. 

Atropine (XXVIII) had already been prepared from ( + )-acetyltropoyl chloride and tropine (40) followed by resolution (41), using n-camphor-sulfonic acid, to obtain first the salt of dextrorotatory hyoscyamine. Recently dibenzoyltartaric acid was claimed to precipitate the salt of the ( —)-antimer first (42). Direct synthesis of hyoscyamine (XXVIII) was realized by melting S-( — )-acetyltropoyl chloride (XXXV), obtained for the first time in crystalline form, with tropine hydrochloride (XXXVI), followed by acid deacetylation of acetylhyoscyamine (XXXVII)... 

Atropine is an ester, and on hydrolysis yields a basic substance, tropine, and optically inactive tropic acid (1). It has been shown that the alkaloid hyoscyamine, which is also obtained from belladonna and is laevo-rotatory, is the ester of tropine with laevo-tropic acid (2), and therefore atropine appears to be racemic hyoscyamine. This view of the nature of atropine has been confirmed by Ladenburg (3), and dextro-hyoscyamine has also been prepared by the union of tropine with dextro tropic acid (4). 

Since hyoscyamine is an ester of the aminoalcohol tropine and (-)-tropic acid, it can therefore be obtained by heating tropine with (-)-tropic acid in the presence of hydrogen chloride as the same manner as atropine (23). 

In the first procedure, hyoscyamine (or atropine) can be selectively determined in the presence of scopolamine by using bromcresol purple, which forms a chloroform-extractable complex with hyoscyamine at pH 6.6. This complex is separated and measured at 420 nm. Scopolamine and the hydrolytic product tropine do not interfere. 

An antiserum was raised by immunization of rabbits with an immunogen prepared by coupling hyoscyamine to human serum albumin and using [3H]-atropine as tracer. Atropine and hyoscyamine reacted to equal extents with the antibodies. Some structurally related drugs e.g. homatropine or scopolamine as well as atropine hydrolysis products (tropine and tropic acid) did not interfere in the assay. 

Accordingly, the stereospecific behavior of the Cs-epimeric tropanols represents decisive evidence for the syw-oriented hydroxyl group of -jior-tropine including its derivatives, e.g., tropacocaine, as well as tigloidine, whereas or-tropine and its alkyl derivative, tropine and its esters, e.g., atropine, hyoscyamine, convolamine, convolvine, poroidine, and iso-poroidine, all (IV) contain anti placed hydroxyl groups (3). 

Atropine. endo-( )-a-< Hydroxy methyl )benzene-acetic acid 8-methyl-8-azabicyclo[3.2.1 oct 3 yl ester, laH,-SaH-tropan 3a-ol (+)-tropate dj-hyoscyamine tropic acid ester with tropine di-tropyl tropate tropine tropate. C17-HjjNOj mo] wt 289.38, C 70.56%, H 8.01%, N 4.84%. O 16.59%. Parasympatholytic alkaloid isolated from Atropa belladonna L, Datura stramonium L, and other Solanaceae. 

From a pharmaceutical point of view, three natural-occurring compounds are widely used as chemotherapeutic agents viz. (-)-hyoscyamine, (-)-scopolamine (hyoscine) and atropine (Fig. 2). The latter compound is formed by the racemization of (-)-hyoscyamine during isolation and purification and is thus ( )-hyoscyamine. All three compounds are esters of 3a-tropine with tropic acid. 

By far the most sensitive test for atropine, Z-hyoscyamine, and Z-scopolamine is their ability to produce mydriasis of the pupil of the eyes of young cats, dogs and rabbits (1). An aqueous, alcohol-free solution of the alkaloid, its sulfate or acetate which must be almost neutral is used. It is dropped into the conjunctival sac of the eye and held so that none is lost by overflow of tears (252). It has been reported (1) that 1 part in 40,000 or that 0.000,000,427 g. of atropine sulfate will cause a distinct dilation of the pupil of the eye in 1 hour. Besides the tropane alkaloids certain digitalis preparations and the volatile base, coniine, possess this same property. Tropine, the basic cleavage product of atropine and Z-hyoscyamine, has no effect upon the eye if administered in the normal way but does possess mydriatic properties when administered internally (252). 

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