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Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.

Publication ,  Journal Article
Feldman, PL; James, MK; Brackeen, MF; Bilotta, JM; Schuster, SV; Lahey, AP; Lutz, MW; Johnson, MR; Leighton, HJ
Published in: J Med Chem
July 1991

In an effort to discover a potent ultrashort-acting mu 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 mu 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-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu 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 mu 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 SAR 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.

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Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

July 1991

Volume

34

Issue

7

Start / End Page

2202 / 2208

Location

United States

Related Subject Headings

  • Time Factors
  • Structure-Activity Relationship
  • Rats, Inbred Strains
  • Rats
  • Piperidines
  • Medicinal & Biomolecular Chemistry
  • Male
  • Humans
  • Guinea Pigs
  • Drug Evaluation, Preclinical
 

Citation

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Feldman, P. L., James, M. K., Brackeen, M. F., Bilotta, J. M., Schuster, S. V., Lahey, A. P., … Leighton, H. J. (1991). Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics. J Med Chem, 34(7), 2202–2208. https://doi.org/10.1021/jm00111a041
Feldman, P. L., M. K. James, M. F. Brackeen, J. M. Bilotta, S. V. Schuster, A. P. Lahey, M. W. Lutz, M. R. Johnson, and H. J. Leighton. “Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.J Med Chem 34, no. 7 (July 1991): 2202–8. https://doi.org/10.1021/jm00111a041.
Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, et al. Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics. J Med Chem. 1991 Jul;34(7):2202–8.
Feldman, P. L., et al. “Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.J Med Chem, vol. 34, no. 7, July 1991, pp. 2202–08. Pubmed, doi:10.1021/jm00111a041.
Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics. J Med Chem. 1991 Jul;34(7):2202–2208.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

July 1991

Volume

34

Issue

7

Start / End Page

2202 / 2208

Location

United States

Related Subject Headings

  • Time Factors
  • Structure-Activity Relationship
  • Rats, Inbred Strains
  • Rats
  • Piperidines
  • Medicinal & Biomolecular Chemistry
  • Male
  • Humans
  • Guinea Pigs
  • Drug Evaluation, Preclinical