Physostigmines

Isaksson and Kissinger (1987) detected physostigmine in plasma with a different system. Physostigmine was eluted on a C-8 column using an acidic eluent with an ion-pairing reagent. This detection system was based on the redox mode, where a dual-electrode thin-layer cell was used in a series configuration, i.e., the reduction current from the second electrode was measured. 

Sparteine is an alkaloid obtained from lupin beans with antiarrhythmic and oxytocic properties. It has a tetracyclic aliphatic structure with two tertiary alicyclic nitrogens. Since sparteine does not contain a chromophore, it cannot be detected with UV or FL. Therefore, Moncrieff (1990) developed a method of detecting sparteine, and its dehydro metabolites, in urine with 

She found that these compounds could be oxidized even in an acidic eluent. Satisfactory elution was achieved on a cyano column at pH 2.5. The eluent had to be quite acidic since extensive peak tailing occurred above pH 4. 

Eseridine [probably identical with geneserine (8)] C15H23O3N3 132 7 

Structure. The methyl carbamate of 5-hydroxy-l,2,3,3a,8,8a-hexa-hydro-l,3a,8-trimethyl pyrrolo [2,3-i]indole. 

Derivatives. A table listing physical constants of derivatives and transformation products of physostigmine is given in Volume II of this series (page 462 ff.). 

Pharmacological action. Widespread effects on the nervous system owing to the inhibition of the enzyme acetylcholinesterase. 

Physostigmine was first isolated by Jobst and Hesse (1) in 1864. The following year, Vee (2) obtained it in crystalline form for the first time and named it eserine (the other common name for the alkaloid). Straus (9) showed that physostigmine contained two AT-methyl groups and behaved as a monoacidic tertiary base. 

2 Examples of Active Areas of Structure Based Design 

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Carbamate Insecticides. These are stmcturaUy optimi2ed derivatives of the unique plant alkaloid physostigmine [57-47-6] a cholinergic dmg isolated in 1864 from Phjsostigma venenosum (see Alkaloids) (17,24,35—39). The carbamates maybe considered synthetic derivatives of the synaptic neurotransmitter acetylcholine, with very low turnover numbers. The A/,A/-dimethylcarbamates of heterocycHc enols (36) and the Ai-methylcarbamates of a variety of substituted phenols (35) with a wide range of insecticidal activity were described in 1954 (35). The latter are the most widely used carbamate insecticides, and the A/-methylcatbamates of oximes have subsequentiy been found to be effective systemic insecticides. 

Heptylphysostigmine (eptastigmine) (17) has been shown to be as active as physostigmine in AChE inhibition, but superior to physostigmine in terms of oral bioavadabihty and half-life (118—120). However, further clinical evaluation of this compound has been halted because of dmg-related hematological toxicity. 

The simpler substance apoharmine according to Flury causes increased reflex excitability in the dog. In the frog it produces a like effect which with larger doses goes on to tetanus. Esterification of harmol with methylcarbamic acid induces affinities with the physostigmine type of drug. ... 

Physostigmine (Eserine), CijHjjOjNa. The alkaloid is best prepared in the laboratory by Salway s process. Methods of manufaetiu e are described by Chemnitius and by Sehwyzer. ... 

Physostigmine dissolves in nitric acid to a yellow solution, which on warming becomes red and on evaporation to dryness leaves a green residue. A neutral solution of the sulphate gives with dilute solution of sodium hydroxide a white precipitate, which gradually becomes pink and dissolves in excess of the alkali, forming a reddish solution, which eventually becomes yellowish-green. 

Johnson has described a method for the estimation of physostigmine in the salicylate for the determination of minute amounts of the alkaloid Ellis, Plaehte and Straus have devised processes depending on (a) inhibition of serum choline-esterase by the alkaloid, or (b) measurement of the colour intensity produced by the conversion of physostigmine to rubreserine in an alkaline medium. i ... 

XXXVIII), m.p. 128°, identical with the product obtained from physostigmine (XXXIX), and, as the latter had already been synthesised from 1-eseroline by Polonovski and Nitzberg,i the work of the American authors constituted the first complete synthesis of physostigmine. 

Physovenine, Cl4Hig03N2, was obtained by Salway from the mother liquors left after the separation of eseramine. It crystallises from a mixture of benzene and light petroleum in small, colourless prisms, m.p. 123°. Its salts are dissociated by water. With barium hydroxide physovenine liberates carbon dioxide and assumes a deep red colour, and, owing to the similarity of this behaviour with that of physostigmine, Salway suggested that physovenine may be an intermediate product in the formation of eseroline from physostigmine. 

Ellis, Krayer and Plachte have shown that the degradation products of physostigmine, eseroline and eserine-brown do not inhibit choline-esterase, but rubreserine and eserine-blue are inhibitors in vitro, having... 

The miotic effect induced by physostigmine lends itself to investigation of the interrelation of chemical constitution and pharmacological action, and Stedman has devoted much attention to this subject. Eseroline is devoid of miotic activity, so that the latter action in physostigmine must be mainly due to the fact that it is a methylurethane, and, since activity only becomes evident in the urethanes of phenolic bases or phenols with a basic side-chain, a basic nucleus for the urethanes appears also to be essential. 

A further development of this subject is due to Aeschlimann and Reinert, who found that in the series represented by (XLI) thedimethyl-carbamic ester (XLI R = Me) and the methylphenylcarbamic ester (XLI R = Ph) were at least as active as physostigmine in stimulating peristalsis. The miotic activity of the dimethylcarbamic ester (prostig-mine, neostigmine) is similar to that of physostigmine, that of the methylphenylcarbamic ester being weak. 

Physostigmine can be regarded as the methylcarbamate of a -amino-phenol, with an alkyl chain substituent in the o-position, relative to the amino-group. Stevens and Beutel, with this in mind, have prepared substances of the type p-RjRjjN, CO, O. CgHjR. NMCjX, where R is an alkyl radical, c.gi, isopropyl, in either the o or m-positioQ relative to the... 

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