Pilocarpine derivatives

Prodrugs have been designed to improve corneal absorption. This approach has been applied with epinephrine (226-230), terbutaline (231), various prostaglandins (232), phenylephrine (233-235), and pilocarpine (236-241). For some pilocarpine derivatives the double prodrug approach has been used to overcome eye irritation and improve on poor water solubility (240,241) (Section 5.4). 

Note It is possible to differentiate amino acids by color on the basis of the markedly different shades produced [2, 3]. Proline and hydroxyproline, that only react weakly with ninhydrin, also yield pink-red colored derivatives [2]. Ergot alkaloids and LSD are detected by spraying with 10% hydrochloric add and then heating to 110°C for 20 min after they have been treated with the reagent [9]. Ergot alkaloids and LSD yield red to purple zones when treated in this manner other alkaloids, e.g. reserpine, emetine, quinine, strychnine, pilocarpine, atropine, scopolamine, cocaine and opium alkaloids, do not give a reaction [9]. 

When (R,R)-Me-Duphos, (R,R,R,R)-BICPO [9] or BINAP [10] is used, the rhodium-catalyzed asymmetric cycloisomerization of 3 affords 4 with up to >99.5% enantiomeric excess (Scheme 7 2). This methodology was applied to the synthesis of functionalized a-methylene-y-butyrolactone derivatives 6 such as (-i-)-pilocarpine 7 (Scheme 7.3) [11]. 

The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline Figure 7-3) are well absorbed from most sites of administration. Nicotine, a liquid, is sufficiently lipid-soluble to be absorbed across the skin. Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines but is nevertheless toxic when ingested—eg, in certain mushrooms—and it even enters the brain. Lobeline is a plant derivative similar to nicotine. These amines are excreted chiefly by the kidneys. Acidification of the urine accelerates clearance of the tertiary amines. 

Pilocarpine has long been used to increase salivary secretion. Cevimeline, a quinuclidine derivative of acetylcholine, is a new direct-acting muscarinic agonist used for the treatment of dry mouth associated with Sjogren s syndrome and that caused by radiation damage of the salivary glands. 

Vianna EP, Ferreira AT, Dona F, Cavalheiro EA, Silva Fernandes MJ (2005) Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats. Epilepsia 46(Suppl 5) 166-173 Volpini R, Costanzi S, Lambertucci C, Taffi S, Vittori S, Klotz KN, Cristalli G (2002) N(6)-alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A(3) receptor and a starting point for searching A(2B) ligands. J Med Chem 45(15) 3271-3279... 

Cholinergic facilitation—e.g., postganglionic cholinergic stimulants, such as acetylcholine, other choline derivatives, and pilocarpine. 

Jaborandi leaves (Pilocarpus microphyllus and P. jaborandi Rutaceae) are also probably derived from histidine, but experimental data are lacking. Jaborandi leaves contain primarily pilocarpine and pilosine (Figure 6.112). Pilocarpine is valuable in... 

Pilocarpine is unique among the cholinergic agents in that it is a tertiary amine derivative, whereas the majority of the members of this class are quaternary ammonium compounds. It has been demonstrated (104,105) that pilocarpine loses its activity when it is measured at pH 9, whereas acetylcholine does not, suggesting that pilocarpine acts in its ionized form, i.e., its activity decreases with increasing pH. 

Derivatives of pilocarpine such as the hexa-decanoyloxymethylene chloride (VIII) similarly show the advantages of the epinephrine prodmg. 

A general review on the use of electrochemical methods for the synthesis of N-heterocycles and natural products includes a section on imidazole derivatives. Thin-layer chromatographic methods for the separation of imidazole alkaloids have been briefly reviewed. Pharmacological effects of pilocarpine (15) have been summarized as part of an excellent review on convulsant alkaloids. ... 

A number of pilocarpine salts (23 X = O or NOH R = NO2, Br, CeHs, or F) have been subjected to D2O exchange experiments in [ HejDMSO and under basic conditions. Compounds (23 X = 0) showed rapid exchange of the a-CH2CO protons. In contrast, oxime derivatives (23 X = NOH) exhibited exchange at C-2,... 

In contrast to pilocarpine, arecoline acts at nicotinic receptors as well as at muscarinic sites it has been described (172) as a partial agonist at and Mg receptors. Arecoline is equipotent to its quaternary analog, iV-meth-ylarecoline, as a muscarinic agonist (172). The secondary amine, norarecoline, is a somewhat weaker muscarinic agonist than arecoline (173,174). The muscarinic activity of esters of arecaidine (the free carboxylic acid derivative... 

To improve the sensitivity of the pilocarpine analysis - enabling determinations in biological fluids - Mitra et al.7 developed a derivatization technique by means of which pilocarpine was quaternarized with the aid of -nitrobenzylbromide (0.25 mg/ml - 24 hrs at 40°C). The quaternary derivatives were analyzed on an octadecyl column using 0.001 M sodium octane-sulfonate in methanol - water (4 1) as mobile phase, the derivatization technique described was also applicable to other amines. 

---