Z-Hyoscyamine

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. 

Cushny has compared the action of d- and Z-hyoscyamines with that of atropine, and of d-homatropine with that of dZ-homatropine in antagonising the action of pilocarpine, and finds that the order of activity of the first three is in the ratio 1 40 20, and of the second two in the ratio 4 2-5. He drew attention also to the important influence of the acyl radical in the tropeines, which exercises the maximum effect when it is a hydroxyalkyl aromatic residue and is laevorotatory and in illustration of this point gives the following table of relative activities on the basis of capacity to antagnonise pilocarpine in the salivary fistula dog —... 

The pharmacology of these three stereo-isomerides, o -hyoscyamine, Z-hyoscyamine, and the racemic form, atropine, has been investigated by Cushny, (5) using the frog as the subject of the experiments. It was found that all three were alike in certain respects, but that with regard to some aspects of their action dextro-hyoscyamine was the strongest and the levo variety the weakest, while with other effects of the drug exactly the reverse was the case. In all cases the action of atropine was intermediate between that of the two optically active forms, and this fact is explained by Cushny by the assumption that atropine is probably decomposed in solution into its two active components. 

The evidence available at the present time suggests that the nitrogen of Z-hyoscyamine and its allies may be derived from the 6-amino group of arginine and ornithine. Of the further stages of the conversion and of the sources of the other parts of the alkaloid molecule, nothing certain is yet known. 

Dry weight g. per plant Assay Mg. Z-hyos-cyamine per plant Total N % dry wt. G. Total N per plant Z-Hyoscyamine-N % total N... 

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). 

The most frequently used color reactions are those developed by Vital and Gerrard and may be briefly described as follows The Vitali Reaction (1). A minute quantity (as little as 0.0001 mg. is sufficient) of solid atropine, Z-hyoscyamine or Z-scopolamine, on a watch glass, is treated with a drop of fuming nitric acid and the liquid evaporated to dryness at 100°. The residue when treated with a drop of freshly prepared solution of ethanolic potassium hydroxide develops a bright purple coloration which slowly fades to a dark red and finally to a colorless liquid. The color sequence can be reproduced by the addition of more potassium hydroxide reagent. 

The same color display is observed in the case of the modified Vitali test. The alkaloid is ground with sodium nitrate and moistened with sulfuric acid, and subsequently treated with potassium hydroxide reagent. This color reaction has been applied to sixty alkaloids and only veratrine Z-Scopolamine will be used throughout this chapter in preference to Z-hyoscine so as to avoid any possibility of confusion of this alkaloid with Z-hyoscyamine. 

The separation of atropine, Z-hyoscyamine and Z-scopolamine has been effected by the fractional crystallization of their aurichlorides. It has been pointed out, however, that the solubility relations of these derivatives are dependent upon impurities and the relative amoimts of each present in the mixture (50). The bases may be recovered by decomposing an aqueous solution of the aurichloride with hydrogen sulfide and filtering to remove the gold sulfide. The base is liberated by addition of potassium carbonate to the filtrate and extraction with chloroform. An alternate method for the separation of atropine and Z-hyoscyamine (25) is by fractional crystallization of their oxalates from acetone and ether in which the Z-hyoscyamine derivative has the greater solubility. Z-Scopolamine and dioscorine on the other hand are purified through their insoluble hydrobromides. 

These alkaloids react readily with picric and aurichloric acids to give nicely crystalline derivatives which, because of the wide spread in their melting points, are the most satisfactory derivatives for the identification of the individual members of this group of alkaloids. There is also a characteristic difference in the aurichloride crystals of atropine and Z-hyoscyamine (20). Atropine aurichloride is a dull lusterless powder which melts in boiling water while Z-hyoscyamine aurichloride crystallizes in glistening golden-yellow leaflets which do not melt in boiling water. 

Z-Hyoscyamine is the most commonly occurring alkaloid in plants of the Solonaceae family and is usually found associated with varying amounts of Z-scopolamine and in rare cases (50, 60, 225) with small amounts of atropine. 

Z-Hyoscyamine (20) and atropine are isomers having the formula CirHjsOsN. Atropine is optically inactive and proved to be the racemic form of Z-hyoscyamine. Such diverse conditions as heating under vacuum... 

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). 

The 0,AT-diacetylnorhyoscyamine has been prepared by the action of acetic anhydride upon the amine oxide of hyoscyamine (182). In acid the 0-acetate is hydrolyzed but in cold alkali, water is eliminated as well with the formation of V-acetyInorapoatropine (acetic anhydride upon the amine oxide of atropine reacts in an analogous fashion). Norhyoscyamine, like hyoscyamine, is easily racemized in alcoholic sodium hydroxide to the optically inactive noratropine (XXIV, R = H). Noratropine and norhyoscyamine are converted with methyl iodide respectively to atropine or Z-hyoscyamine and their methiodides (209). 

The relation of the various transformation products of Z-hyoscyamine and atropine is summarized schematically in Chart II. 

When Z-scopolamine (Z-hyoscine) is warmed with barium hydroxide (52, 56, 232), dilute alkalies (232), or acids (60, 212) it is hydrolyzed to tropic acid and a new base (CsHisOjN), scopoline (oscine). Depending on the conditions of the experiment, the tropic acid recovered may be either the pure Z-form or the partially racemized acid, or may even be dehydrated to atropic acid (52, 64, 232). The scopoline isolated from these experiments is invariably optically inactive (212). By analogy with Z-hyoscyamine, Z-scopolamine would appear to be a base (scopoline) in which the alcoholic... 

The analogy of Z-scopolamine with Z-hyoscyamine is not complete, failing in several instances ... 

Bellaradine (C7H13ON) (225), an oily base isomeric with nortro-pine, is present to the extent of 0.008% along with Z-hyoscyamine, Z-scopola-mine, and tropine in Bulgarian belladonna root. Its strong basic properties were employed in its separation from this mixture of alkaloids. It forms a crystalline and weakly Zeyorotatory hydrochloride which, like tropinone and... 

The alkaloids of the tropane group show a series of common chemical characteristics, particularly that of being esters of organic acids combined with bicyclic hydramines. They include Z-hyoscyamine and its isomer atropine, cocaine, scopolamine or hyoscine, and a series of secondary alkaloids. 

The chief representatives of this group are the tropane alkaloids, atropine, its fero-isomer, Z-hyoscyamine, and Z-scopolamine (Z-hyoscine). They are all powerful mydriatic and cycloplegic drugs. Atropine is the most important in ophthalmology, and it is usually used as its neutral sulfate in 1% solution. When such a solution is instilled into the human eye, mydriasis begins in about half an hour and is complete in about an hour ... 

In the mouse eye (after intraperitoneal injection) Ing et al. (2) found that the metho-salts of atropine and Z-hyoscyamine were at least twice as active as their parent alkaloids, but Z-scopolamine methiodide was about equal in activity to Z-scopolamine hydrobromide on the other hand, in the anesthetized cat, Z-scopolamine methiodide, injected intravenously, was about 60% more active as a mydriatic than Z-scopolamine. When the same compounds were applied locally to cats eyes, the parent alkaloids were invariably more active than the corresponding metho-salts. 

It therefore appears that the metho-salts of atropine, Z-hyoscyamine, and Z-scopolamine are intrinsically more active at parasympathetic nerve endings than their parent alkaloids, but that when the drugs are applied locally to the eye the parent alkaloids may appear to be more active than their metho-salts. The weaker activity of the metho-salts on local application to the eye is probably due to their less ready absorption from the conjunctival sac, since quaternary salts are well known to penetrate cell membranes less readily than the salts of tertiary bases. Tertiary bases can penetrate cell membranes either as the cation, R3NH+, or as the unionized base, R3N, and in general it can be said that the latter penetrates more readily than the former. 

Atropine is the racemic form of the alkaloid /-hyoscyamine. The latter is a common tropane alkaloid found in solanaceous plants, such as belladonna (Atropa belladonna), henbane (Hyoscyamus niger), and the deadly nightshade (Datura stramonium). During extraction, Z-hyoscyamine is readily racemized to atropine, which does not occur naturally in more than traces. 

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