WATER-SOLUBLE SALTS OF AMINO-ACID ESTERS OF THE ANESTHETIC AGENT PROPOFOL

The glycinates 4, 5, acetates 6, 7, 10, propionate 8, butyrate 9 and c arbonate 11 were synthesized and evaluated as potential water-soluble prodrugs of Propofol (2,6-diisopropylphenol) 1 suitable for parenteral administration. The 4-9 . HCl salts were also prepared and some of th em (i.e. 4 . HCl and 6 . HCl) were found sufficiently soluble in aqueo us solutions. The kinetics of hydrolysis of the esters 4-11 and 4-9 . HCl salts were studied in 0.05 M phosphate buffer pH 7.4, and a number of derivatives (4, 6, 7, and corresponding HCl salts) were examined f or their stability in human plasma and brain homogenate. Our results i ndicated that the salts 4 . HCl and 6 . HCl, sufficiently soluble in w ater, are relatively stable in physiological media. Most of the examin ed compounds, in particular compound 6, were found to inhibit the bind ing of [S-35]-tert-butylbicyclophosphorothionate (S-35]TBPS) demonstra ting to possess affinity for the Propofol recognition site on GABA(A) receptors. (C) 1998 Elsevier Science B.V. All rights reserved.