The Jaborandi Alkaloids

The name Jaborandi has been applied to a number of closely related South American plants of the order Rutaceae, which have aroused great interest because of their valuable pharmacological properties. The drug was first sent to Europe from Pernambuco by a Dr. Coutinho in, 1874, and the botanical source of most of the earlier samples was subse- 

Botanical name Commercial name or source Alkaloids present Percentage total alkaloid (on dry wt.) Percentage pilocarpine isolated as nitrate Refer- ences 

Four well-defined alkaloids, pilocarpine (I), its stereoisomer isopilocarpine, pilocarpidine (II) and pilosine (III), have been isolated from jaborandi and their structures have been fully elucidated. In addition, 

Petit and M. Polonovski (49) reported the isolation from P. spicatus 

of two further alkaloids, i -pilocarpine and i -jaborine both were amorphous, optically inactive bases which were not completely characterized. D. Parodi (22) described the isolation of a weak base, jaborandine, C20H12O6N2 ( ), melting point 110°, from a sample of Paraguay jaborandi derived from a Piper species, and E. Harnack and 

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The Jaborandi alkaloid pilocarpidine (49) is the A -nor lower homolog of pilocarpine. No new reports on the occurrence of pilocarpidine have been published since the last review in this series (1). The synthesis of pilocarpidine that terminates with the N -methylation of the imidazole nucleus is likewise the synthesis of pilocarpidine (Section III,F). 

VI. Tables of Physical Constants of the Jaborandi Alkaloids, Their Derivatives... 

No detailed directions for the isolation of the jaborandi alkaloids on the laboratory scale appear to have been published, but F. Chemnitius... 

Davies SG, Roberts PM, Stephenson PT, Storr HR, Thomson JE (2009) A practical and scalable total synthesis of the jaborandi alkaloid (-l-)-pilocarpine. Tetrahedron 65 8283-8296. doi 10.1016/j.tetlet.2009.03.021... 

The basic alkaloid in Pilocarpus jaborandi (Rutaceae) is pilocarpine, a molecule of which contains an imidazole nucleus and is also used as a clinical drug. During alkaloid synthesis, L-histidine can produce the manzamine nucleus (Figure 27). These alkaloids are quite widespread, though they were first isolated in the late 1980s in marine sponges. They have an unusual polycyclic system and a very broad range of bioactivities. Common alkaloids with this nucleus include manzamine A, manzamine B, manzamine X, manzamine Y, sextomanzamine A and so on. 

In order to avoid the undesirable isomerization to isopilocarpine (Section III,D,3) and, probably, to avoid enzymatic degradation, the Jaborandi leaves are processed as rapidly as possible. Acidification converts the alkaloids to their water-soluble salts, which allows defatting of the leaves with, for example, petroleum ether. Alkalinization and extraction with a suitable lipid-extracting solvent or solvent mixture gives the crude alkaloid mixture. (+)-Pilocarpine (mp 34°C) crystallizes only with difficulty it can be obtained readily as the nitrate salt (mp 178°C) in the absence of isopilocarpine. The separation of isopilocarpine nitrate from pilocarpine nitrate by crystallization is often difficult because mixtures may give products of constant melting points the same holds for the hydrochlorides. 

Pilocarpine—is the principal alkaloid of jaborandi. It forms a colorless, amorphous mass, readily soluble in water, alcohol, ethes, and chloroform. It readily foms snlta Its chloride—Pil tcarpince hy-droc/thras t 5.—occurs iu white, deliquescent, odorless ciystals. 

The presence of alkaloids in jaborandi was first reported by M. Byasson (73) and the principal alkaloid, pilocarpine, was isolated independently by A. W. Gerrarci (74-77) and E. Hardy (78) both of whom characterized it by the preparation of several crystalline salts. A. Petit and M. Polonovski (50) showed the presence of a second alkaloid, isomeric with pilocarpine although pilocarpine is easily converted into the new base under a variety of conditions (see Section 5), they maintained that it also occurs in the leaves and is not purely an artifact formed during the isolation processes. Jowett (28) named this base isopilo-... 

EFFECT OF ACID AND ALKALI ON THE OPTICAL ROTATORY POWER OF THE MINOR JABORANDI ALKALOIDS AND THEIR DERIVATIVES... 

CiiHi NjOa, Mr 208.26, oily liquid or crystals, mp. 34 °C (as hydrochloride 193-205 °C, nitrate I74°C), bp. 260°C (0.7 kPa), [a] > +106° (HjO), soluble in water, ethanol, chloroform forms well crystallizing salts with acids. P. is the main alkaloid of the South American jaborandi tree (Pilocarpus jaborandi). It is isolated from the leaves. P. is also easily accessible by synthesis and is used as its salts in medicine as a cholinergic parasympathicomimetic, miotic (for glaucoma) agent and as an atropine antagonist it is also used in veterinary medicine for colics and constipation. Detection by means of Helch s reaction. Pilocarpus species contain further imidazole alkaloids (see table). 

This is undoubtedly the most important class of L-histidine derivatives only because of pilocarpine s (27) therapeutic uses [8, 23, 24]. Since Byasson s first report of jaborandi alkaloids isolation from the leaves of Pilocarpus spp. (Rutaceae) [8], in 1875, several other imidazole alkaloids have been reported in this genus. The identification of these was facilitated due to recent advances in hyphenated chromatographic techniques such as HPLC—ESI—MS/MS (high performance liquid chromatography with electrospray ionization tandem mass spectrometry). 

Elvidge developed the colorimetric method for the determination of small quantities of jaborandi alkaloids which, with the exception of apomorphine appeared to be specific for the glyoxaline group. 

The test was also carried out with other alkaloids of jaborandi, iso pilocarpine, pilocarpidine and pilosine, to ascertain whether they are equally chromogenic with pilocarpine. With the exception of the pilosine, these were found to give the same colour as pilocarpine. Since the alkaloids present in jaborandi consist principally of pilocarpine and wopilocarpine with smaller quantities of the other alkaloids, it would appear that the colorimetric method should be capable of giving reasonably accurate results in the determination of the total alkaloids of the drug calculated as pilocarpine. 

The extraction of alkaloids from jaborandi has been dealt with by Wurtzen, and the estimation of pilocarpine in the drug and its preparations by Jowett and by Bourcet and more recently by Taran and by Shupe.ii Elvidge has devised a colorimetric method based on Ekkert s test, < and a polarographic study has been made by Kirkpatrick. Tlie two first-pamed authors depend on the isolation of pilocarpine nitrate, which is also the basis of the process of manufacture described by Cheninitius.12... 

Pilocarpidine, CiqHiiOjNj. This alkaloid was obtained by Harnack from P. Jaborandi, and later by Merck from the mother liquors from crystallisation of pilocarpine nitrate. It does not occur in the leaves of P. microphyllus (Jowett, ). The free base is a viscid oil, [a]n + 81-3° (less in presence of alkali). The salts crystallise well the nitrate, B. HNO3, in colourless prisms, m.p. 137°, - -73-2°. The aurichloride, unlike... 

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pilocarpus jaborandi) and arecoline (from Areca catechu betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma... 

Pilocarpine (30) is one of a series of related alkaloids found in the South American plant genus Pilocarpus, known commonly as Jaborandi leaf, which was used in traditional medicine to induce sweating and urination. The molecular structure of (30) bears similarities to ACh (2) since the positively-charged N-atom and the lactone binding to the serine are about the same distance apart. Chewing the leaf results in typical features... 

The kinetics of the hydroxide ion-catalyzed epimerization of pilocarpine to isopilocarpine and of its hydrolysis to pilocarpic acid have been studied (56). Both forms of degradation lead to loss of pharmacological activity. The importance of possible inactivation by epimerization during thermal sterilization of ophthalmic preparations of pilocarpine was pointed out. It was also considered that some epimerization would always occur during the extraction of pilocarpine from Jaborandi leaves, and that isopilocarpine might, therefore, be an artifact and not a genuine plant alkaloid (55). 

Histidine is a precursor of a very limited number of alkaloids. The most well-known is pilocarpine from Pilocarpus jaborandi. The plant was formerly used as a truth serum (diaphoretic activity), and the alkaloid is used to counter the mydriatic effects of atropine. 

The leaves of Pilocarpus species, including Pilocarpus jaborandi (jaborandi) and Pilocarpus racemosus (acei-tillo), contain pilocarpine or isopilocarpine as major alkaloids as well as a variety of minor alkaloids. Pilocarpine (see separate monograph) is an agonist at acetylcholine receptors, which enhances salivary flow, sweating, and gastrointestinal motility. It can interfere with asthma therapy and the effect of anticholinergic drugs. 

Pilocarpine Hydrochloride, USP. Pilocarpine mono-hydrochloride is the hydrochloride of an alkaloid oblaineil from the dried leaflets of Pilocarpus jaborandi or P. micro-pliylltis, in which it occurs to the extent of about 0.39 together with other alkaloids. 

Herbal substitutes for dru [s of abuse A variety of herbal mixtures are offered for sale in magazines, on the internet and in so-called smart , eco or head shops. Many are marketed as herbal Ecstasy and the plants included in the formulations include Yohimbe bark, Kava-Kava (Piper methysticum),Y-3 e.emi, Hops, Jaborandi and Alisma. One product contains Kava-Kava, Guarana, Uva Ursi and Cascara bark. Many of the products sold as herbal Ecstasy contain either Ephedra sinica (Ma huang) or the Indian plant Sida cordifolia which both contain the alkaloid ephedrine (see R03c, Chapter VI). Other alkaloids may also occur, such as pseudoephedrine, norephedrine and norpseudoephedrine. The side-effects of ephedrine include tachycardia, anxiety, insomnia and arrythmias and a hypotensive crisis may develop if monamine oxidase inhibitors are also taken. Many adverse reactions and more than 20 deaths have been attributed to ephedrine and Ephedra consumption. Research conducted in the US shows that the daily intake of some Ephedra products would give ephedrine levels well above the recommended therapeutic doses. 

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