NEW WATER-SOLUBLE PILOCARPINE DERIVATIVES WITH ENHANCED AND SUSTAINEDMUSCARINIC ACTIVITY

The synthesis of an homologous series of new water-soluble derivatives of pilocarpine is described. The new compounds, referred to as soft q uaternary salts, are water soluble by virtue of a cationic ammonium he ad and their lipophilicity can be modulated by manipulating the size a nd the nature of the substituent in the inactive portion of the molecu le. The miotic activity of the compounds was evaluated after administr ation to normotensive New Zealand White rabbits. Changes in pupil size indicated a substantial cholinergic effect on the iridal sphincter mu sculature. The best candidate, compound 20, which has a 16-carbon side chain, was evaluated for reduction of the intraocular pressure in gen etically glaucomatous Beagles. Compound 20 is superior to pilocarpine in both tests, with a potency 10 to 20 times that of the parent compou nd and a longer duration of action. It is suggested that the new compo unds are pro-drug forms of pilocarpine which greatly enhance the corne al bioavailability of the parent compound.