Abstract
We describe a simple method for calculating the pharmacological activity of an agonist (A) relative to a standard agonist (S) using only the concentration-response curves of the two agonists. In most situations, we show that the product of the ratios of maximal responses (E max − A/E max − S) and potencies (EC50 − S/EC50 − A) is equivalent to the product of the affinity and intrinsic efficacy of A expressed relative to that of S. We refer to this term as the IRA value of A. In a cooperative system where the concentration-response curve of the standard agonist is steep and that of the test agonist is flatter with a lower maximal response, the simple calculation of IRA described above underestimates agonist activity; however, we also describe a means of correcting the IRA in this situation. We have validated our analysis with modeling techniques and have shown experimentally that the IRA values of muscarinic agonists for stimulating contractions in the guinea pig ileum (M3 response) are in excellent agreement with those measured in the phosphoinositide assay on Chinese hamster ovary cells expressing the M3 muscarinic receptor.
Footnotes
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Send reprint requests to: Frederick J. Ehlert, Ph.D., Department of Pharmacology, College of Medicine, University of California–Irvine, Irvine, CA 92697-4625. E-mail:fjehlert{at}uci.edu
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↵1 This work was supported by National Institutes of Health Grant NS30882.
- Abbreviations:
- CHO
- Chinese hamster ovary
- EAMR
- equiactive molar ratio
- Emax
- maximal response
- IRA
- intrinsic relative activity
- KRB
- Krebs-Ringer bicarbonate
- McN A-343
- 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium
- MEM
- minimum essential medium
- Received July 29, 1998.
- Accepted December 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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