676259-95-3Relevant academic research and scientific papers
Highly water-soluble derivatives of the anesthetic agent propofol: In vitro and in vivo evaluation of cyclic amino acid esters
Altomare, Cosimo,Trapani, Giuseppe,Latrofa, Andrea,Serra, Mariangela,Sanna, Enrico,Biggio, Giovanni,Liso, Gaetano
, p. 17 - 26 (2003)
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 α-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 [ 35S]tert-butylbicyclophosphorothionate ([35S]TBPS) binding assay or electrophysiological measurements of the action at cloned human receptors, proved to be a mechanism involving allosteric modulation of GABAA receptors. Indeed, L-proline (6a), and racemic pipecolinate (6b) and nipecotate (6c), like propofol, reduced [35S]TBPS binding, whereas isonipecotate (6d) showed bicuculline-like behavior, increasing [ 35S]TBPS binding. A nonlinear relation between GABAA 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.
