Z-Scopolamine

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. 

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. 

Datura Metel, in which Z-scopolamine is the chief alkaloid constituent, is used in the technical manufacture of this alkaloid (240). The finely powdered meal is moistened with 10% aqueous potassium hydroxide solution and is extracted with ether. The purified extract is converted to the hydrobromide and crystallized from a mixture of ethanol and acetone. The pure hydrobromide, upon conversion to the free base, gives a crystalline mmiohydrate from ether the anhydrous base is a sirup. 

The Z-scopolamine molecule contains a hydroxyl group because a monoacetate (52, 232) and a monobenzoate (54) can be prepared. The basic nitrogen of this alkaloid must be tertiary since it is recovered unchanged from the action of sodium nitrite upon its hydrochloride and tunce it reacts with but one mole of methyl iodide in the formation erf the... 

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 ... 

The conclusion that scopoline is not the primary hydrolysis product of Z-scopolamine proved to be Avell founded in that its hydrolysis by a... 

LXIV). Scopine is readily converted by either acid or base to scopoline (174). Hence Z-scopolamine must be 1-tropylscopeine (LXVI). 

Pseudoscopine (LXV), the analog of pseudotropine, is derived from Z-scopolamine by a novel reaction. The quaternary salt, scopinium tropate, 0 CH2OH... 

LXVIII, X = O-C-CH-CeHs), was formed in 20% yield as well as the amine oxide when Z-scopolamine reacted with hydrogen peroxide (183, 190) and was isolated as the bromide, X = Br. Moist silver oxide liberated a IH-... 

A number of alkaloids occur in small amounts associated with Z-hyos-cyamine, Z-scopolamine and Z-cocaine which find no place in the previoiis narrative and, although some of them are not tropane derivatives, they will be briefly mentioned in alphabetical order. 

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 ... 

Similar results were obtained for scopolamine. Cushny and Peebles (8) found that Z-scopolamine was about twice as active as the racemic compound on the heart, the salivary gland, and the eye. Later experiments (9) in which d- and Z-scopolamines were compared directly on these organs, and as antagonists of pilocarpine in the gut, showed that the Zeyo-isomer was some 16-18 times as potent as the dextro. 

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. 

Mintzer, M.Z. and Griffiths, R.R., Lorazepam and scopolamine a single-dose comparison of effects on human memory and attentional processes, Exp. Clin. Psychophatmacol., 11, 56, 2003. 

Nachum Z, Shahal B, Shupak A, et al. Scopolamine bioavailability in combined oral and transdermal delivery J Pharmacol Exp Ther. 2001 296 121-123. 

Nevertheless, reliable methods using the SIM mode were introduced for TA analysis. The SIM mode was used for analysis of atropine and scopolamine from human viscera [15] and human plasma [11] (Table 8), of tropisetron from liver microsomal incubation mixtures [82] (Table 7), of granisetron from rat plasma [72], of hyoscyamine enantiomers from human plasma [48], of scopolamine from rabbit plasma [89], of tiotropium from human plasma [81] (Table 5) and of atropine from dog plasma [96] (Table 6). The corresponding values for the monoisotopic molecular weight (MW) and the corresponding m/z-val ucs of protonated TTA and pure QTA are summarized in Table 9. 

Gao, Y Tang, X. C. Guan, L. C. Kuang, P. Z. Huperzine A reverses scopolamine-and muscimol-induced memory deficits in chick. Acta Pharmacol. Sin., 2000, 21 1169-1173. 

Liu T, Xia Z, Zhang WW, Xu JR, Ge XX, Li J et al (2013) Bis(9)-(-)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice. Pharmacol Biochem Behav 104 138-143... 

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. 

Jaremicz Z, Luczkiewicz M, Kisiel M, Zarate R, El Jaber-Vazdekis N, Migas P. Multi-development-HPTLC -method for quantitation of hyoscyamine, scopolamine and their biosynthetic precursors in selected Solanaceae plants grown in natural conditions and as in vitro cultures. Phytochem Anal 2014 25(l) 29-35. 

Li Z, Guo YY, Wu CP, Li X, Wang JH. Protective effects of pseudoginsenoside-Fll on scopolamine-induced memory impairment in mice and rats. J Pharm Pharmacol 1999 51 435-440. 

M. and M. Polonovski found that when scopolamine is treated with hydrogen peroxide, there is formed in addition to scopolamine. Z-oxide [a]i, — 14° (HjO), [B. HBr, m.p. 153°] the quaternary base scopinium, isolated in the form of its bromide, m.p. 209-10°. The latter is reduced by sodium amalgam to a tertiary base, stereoisomeric with scopine and related to the latter as 0-tropine is to tropine and, therefore, named Ji-scopiNE. It yields crystalline salts B. HCl, m.p. 257-8°, aurichloride,... 

Example Plant alkaloids can be identified from DESI mass spectra of seeds, leaves, flowers, or roots. Here seeds of deadly nightshade Atropa belladonna) were subjected to DESI for the identification of their principal alkaloids atropine and scopolamine (Fig. 13.6) [13]. (Atropine is the name of the racemic mixture of (R)- and (S)-hyoscyamine. It is a tropane alkaloid also extracted from jimsonweed Datura stramonium), mandrake Mandragora officinarum) among other plants of the Solanaceae family.) The inset in Fig. 13.4 shows tandem mass spectra of the ions at m/z 290 and 304, thereby confirming them as corresponding to protonated hyoscyamine and scopolamine, respectively. The confirmation of the ion at m/z 304 as [M+H] ion of scopolamine was obtained by conparing the tandem mass spectrum with that of the standard alkaloid. 

Fig. 13.6. DESI mass spectrum of Atropa belladonna seeds using methanol water =1 1 as spray solvent. The insets show tandem mass spectra of the protonated alkaloids hyoscamine, m/z 290 and scopolamine, m/z 304. Both protonated alkaloids have the characteristic loss of tropic acid, 166 u, in common. Reprinted from Ref. [13] with permission. The Royal Society of Chemistry, 2005.

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