Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vivo evaluation of cyclic amino acid esters

Add time:07/22/2019    Source:sciencedirect.com

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.

We also recommend Trading Suppliers and Manufacturers of 4-Amino Propofol Hydrochloride (cas 100251-91-0). Pls Click Website Link as below: cas 100251-91-0 suppliers

Prev:Distinct actions of etomidate and propofol at β3-containing γ-aminobutyric acid type A receptors
Next:Interactions between opioid drugs and propofol in laboratory models of seizures)