title: Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vivo evaluation of cyclic amino acid esters.
abstract: Cyclic amino acid esters of propofol were synthesized in an attempt to develop new water-soluble anesthetic agents. Their solubility and stability in aqueous solution, and their ability to release propofol in vitro under physiological conditions were determined. L-Proline (6a) and racemic nipecotic acid (6c) esters were found to be highly soluble in water. Sufficiently stable at physiological pH (half-lives >6 h), the alpha-amino acid esters, 6a and 6b, were found to be quantitatively hydrolyzed in plasma and liver esterase solutions within a few minutes, showing prodrug behavior. The in vitro activity of the esters, determined either by the [(35)S]tert-butylbicyclophosphorothionate ([(35)S]TBPS) binding assay or electrophysiological measurements of the action at cloned human receptors, proved to be a mechanism involving allosteric modulation of GABA(A) receptors. Indeed, L-proline (6a), and racemic pipecolinate (6b) and nipecotate (6c), like propofol, reduced [(35)S]TBPS binding, whereas isonipecotate (6d) showed bicuculline-like behavior, increasing [(35)S]TBPS binding. A nonlinear relation between GABA(A) receptor binding affinity and lipophilicity, as assessed by reversed-phase high-performance liquid chromatography, emerged as a trend. The in vivo anticonvulsant and anesthetic activities of prolinate 6a, intraperitoneally administered in water solution, showed that is a water-soluble propofol prodrug candidate for developing formulations useful for parenteral administration.
mesh_terms: D000598:Amino Acids, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004355:Drug Stability; D004952:Esters; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007540:Isonipecotic Acids / Q000737:chemistry; D008297:Male; D009557:Nipecotic Acids / Q000737:chemistry; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000737:chemistry; D015742:Propofol / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water; D014982:Xenopus laevis
chemical_list: D000598:Amino Acids, Cyclic; D018686:Anesthetics, Intravenous; D004952:Esters; D007540:Isonipecotic Acids; D009557:Nipecotic Acids; D011355:Prodrugs; D011963:Receptors, GABA-A; D014867:Water; C030278:nipecotic acid; D011392:Proline; D015742:Propofol