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A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics.

Publication ,  Journal Article
Lutz, MW; Morgan, PH; James, MK; Feldman, PL; Brackeen, MF; Lahey, AP; James, SV; Bilotta, JM; Pressley, JC
Published in: J Pharmacol Exp Ther
November 1994

A simple mathematical model of analgesia in the rat is developed and utilized to determine quantitative structure-activity relationships for a series of novel 4-anilidopiperidine opioids. The compounds tested (selected alkyl carboxyethyl esters attached at the one position of the piperidine ring) were designed for rapid inactivation by blood and tissue esterases. Model parameters included potency and rate constants for loss of pharmacodynamic effect by hydrolysis dependent and independent processes. A significant correlation is observed between duration of pharmacological effect in vivo and the rate constant for hydrolysis in human blood (r = 0.89). In vivo potency shows a moderate correlation with log P2 (r = -0.77). The validity of the model is shown by comparing model-based parameters which characterize potency and duration of effect in vivo with graphically derived parameters. Significant correlations are observed between model and graphically based estimates of potency (r = 0.75) and between model and graphically based estimates of duration of effect (r = 0.70). This model has potential application in studies of other classes of compounds in which hydrolytic cleavage limits duration of pharmacologic effect.

Duke Scholars

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

November 1994

Volume

271

Issue

2

Start / End Page

795 / 803

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Rats, Sprague-Dawley
  • Rats
  • Pharmacology & Pharmacy
  • Narcotics
  • Models, Biological
  • Mathematics
  • Male
  • Kinetics
  • Hydrolysis
 

Citation

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Lutz, M. W., Morgan, P. H., James, M. K., Feldman, P. L., Brackeen, M. F., Lahey, A. P., … Pressley, J. C. (1994). A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics. J Pharmacol Exp Ther, 271(2), 795–803.
Lutz, M. W., P. H. Morgan, M. K. James, P. L. Feldman, M. F. Brackeen, A. P. Lahey, S. V. James, J. M. Bilotta, and J. C. Pressley. “A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics.J Pharmacol Exp Ther 271, no. 2 (November 1994): 795–803.
Lutz MW, Morgan PH, James MK, Feldman PL, Brackeen MF, Lahey AP, et al. A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics. J Pharmacol Exp Ther. 1994 Nov;271(2):795–803.
Lutz, M. W., et al. “A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics.J Pharmacol Exp Ther, vol. 271, no. 2, Nov. 1994, pp. 795–803.
Lutz MW, Morgan PH, James MK, Feldman PL, Brackeen MF, Lahey AP, James SV, Bilotta JM, Pressley JC. A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics. J Pharmacol Exp Ther. 1994 Nov;271(2):795–803.

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

November 1994

Volume

271

Issue

2

Start / End Page

795 / 803

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Rats, Sprague-Dawley
  • Rats
  • Pharmacology & Pharmacy
  • Narcotics
  • Models, Biological
  • Mathematics
  • Male
  • Kinetics
  • Hydrolysis