Newly Published
Classic Papers Revisited  |   February 2020
Insights into the Chemical Discovery of Remifentanil
Author Notes
  • From Discovery and Translational Medicine, Intarcia Therapeutics, Inc., Research Triangle Park, North Carolina.
  • Submitted for publication November 30, 2019. Accepted for publication December 17, 2019.
    Submitted for publication November 30, 2019. Accepted for publication December 17, 2019.×
  • Correspondence: Address correspondence to Dr. Feldman: 6 Davis Drive, P.O. Box 12878, Durham, North Carolina 27709. paul.feldman@intarcia.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Classic Papers Revisited / Pain Medicine / Pharmacology / Opioid
Classic Papers Revisited   |   February 2020
Insights into the Chemical Discovery of Remifentanil
Anesthesiology Newly Published on February 4, 2020. doi:https://doi.org/10.1097/ALN.0000000000003170
Anesthesiology Newly Published on February 4, 2020. doi:https://doi.org/10.1097/ALN.0000000000003170
Abstract

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.

In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure–activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.