Pilocarpine structure

Initially, pilocarpine structure was incorrectly attributed as a betaine derivative of a pyridine-lactic acid compound. Further research, based rai chemical degradation, synthesis, and X-ray analysis, provided pilocarpine structure as (25,3/ )-2-ethyl-3-[(l-methyIimidazol-5-yl)methyl]-4-butanolide, as extensively described in previous reviews [8],... 

The three-point pharmacophore models are shown in Fig. 7. The structures of the y0-alanine analogues and their antiepileptic activities against pilocarpine test are tabulated in Table 3. 

Ethylene vinyl acetate has also found major applications in drug delivery. These copolymers used in drug release normally contain 30-50 wt% of vinyl acetate. They have been commercialized by the Alza Corporation for the delivery of pilocarpine over a one-week period (Ocusert) and the delivery of progesterone for over one year in the form of an intrauterine device (Progestasert). Ethylene vinyl acetate has also been evaluated for the release of macromolecules such as proteins. The release of proteins form these polymers is by a porous diffusion and the pore structure can be used to control the rate of release (3). Similar nonbiodegradable polymers such as the polyurethanes, polyethylenes, polytetrafluoroethylene and poly(methyl methacrylate) have also been used to deliver a variety of different pharmaceutical agents usually as implants or removal devices. 

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... 

Pilocarpine is a naturally occurring cholinomimetic alkaloid that is structurally distinct from the choline esters. It is a tertiary amine that crosses membranes relatively easily. Therefore, it is rapidly absorbed by the cornea of the eye, and it can cross the blood-brain barrier. Pilocarpine is a pure muscarinic receptor agonist, and it is unaffected by cholinesterases. Muscarine is an alkaloid with no therapeutic use, but it can produce dangerous cholinomimetic stimulation following ingestion of some types of mushrooms (e.g., Inocybes). 

In 1900 Jowett (38) suggested that the differences between pilocarpine and isopilocarpine had their origin in the steric structures. This was in contrast to the opinion of Pinner et al. who assumed the differences to be caused by N-methylation at different sites in the imidazole ring (39). Lan-genbeck in 1924 assumed on the basis of chemical reactions, such as the formation of quaternary salts and ozonolysis, that the differences were of a steric nature (40,41). Preobrazhenski et al. in 1936 (42) supposed on the basis of different stability and optical rotation that pilocarpine and isopilocarpine should possess the cis and trans configuration, respectively. An identical conclusion was drawn by Zavyalov (43) in 1952, on the basis of... 

Chumachenko et al. (50,51) confirmed the structure of pilocarpine by their synthesis of homopilopic acid, a degradation product of pilocarpine (Section III,F). Inch and Lewis (52) also gave structural evidence by their synthesis of (+)-(/ )- l-acetoxy-2,3-(bisacetoxymethyl)pentane (14), which... 

Although the pharmacological properties of pilocarpine have been studied extensively (106), little is known of the structural requirements for its parasympathomimetic activity. In 1982 Aboul-Enein and Al-Badr published an extensive review on the structure-activity relationship of compounds that are structurally related to pilocarpine (102) this review also gives a prognosis of receptor sites. A general conclusion is that any slight structural modification of the pilocarpine molecule causes a drastic reduction in or complete loss of its biological activity. 

Metapilocarpine was first reported by Pinner he obtained it by heating pilocarpine hydrochloride at 225-235°C (118). Polonovski proposed a betaine structure (58) for the compound (119). On reinvestigation, metapilocarpine was shown to be a racemic mixture of isopilocarpine (120). The structure was proved by spectral analysis and by GLC comparison with authentic isopilocarpine. The pharmacological activity of the racemic product was compared to that of (+)-pilocarpine and (+)-isopilocarpine (120). 

In 1973, Khuong-Huu et al. isolated three alkaloids anantine (94), cyno-metrine (95), and cynodine (96), from the leaves of Cynometra ananta, a plant of the Leguminoseae family native to Zaire. The structures were deduced on the basis of spectral and chemical evidence (752). The structures bear some similarity to that of pilocarpine (7), which contains a lactone ring instead of a lactam ring. Treatment of cynometrine with polyphosphoric acid yielded the N-methylated anantine (97). The latter compound could not be prepared by a simple N-methylation of anantine. Hydrolysis of cynodine afforded cynometrine and benzoic acid. 

Fig. 5 Diagrammatic illustration of a unit of Ocusert system, showing various structural components, and the ocular release rate profile of pilocarpine from the Ocusert pilo-20 system. (From Ref. l)...

The Alza Ocusert device (Fig. 9.39) releases controlled amounts of pilocarpine over a period of 7 days and is designed for the treat-Structure VII Dipivoyl epinephrine (dipivefrine compare ment of glaucoma. It comprises a dmg reser-with Structure VI) voir in which pilocarpine is embedded in an... 

Comparative visual and potentiometric titrations of salts of pilocarpine have been reported. The structurally interesting spinaceamine (24 R = H) and 6-methylspinaceamine (24 R = Me), isolated from amphibian venoms, have been shown to possess antimicrobial activity. ... 

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