Overview of Receptor Interactions of Agonists and Antagonists

Terry Kenakin1

1 GlaxoSmithKline Research Institute, Research Triangle Park, North Carolina
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 4.1
DOI:  10.1002/0471141755.ph0401s42
Online Posting Date:  September, 2008
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Historically, the earliest methods used to quantitatively measure the fundamental properties of drugs (namely affinity and efficacy) employed isolated tissues, and it is in this realm that the null methods used to define “receptor pharmacology” were described. This unit describes these methods and their use to specifically classify agonists (through potency ratios and determination of relative affinities and efficacies) and antagonists (through analysis of surmountable and insurmountable antagonism) to yield estimates of potency. Different drugs can yield different behaviors in various tissues, so this unit is centered on a flow diagram to indicate the type of analysis appropriate for the behavior observed. For example, some agonists may be full agonists in some tissues and partial agonists in others, while some antagonists may demonstrate surmountable simple competitive antagonism in some tissues and insurmountable non‐competitive antagonism in others. Methods exist for determination of affinity and efficacy for all of these behaviors, and these are delineated in this unit. Curr. Protoc. Pharmacol. 42:4.1.1‐4.1.24. © 2008 by John Wiley & Sons, Inc.

Keywords: receptor theory; drug classification; in vitro analysis; affinity; efficacy

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Table of Contents

  • Introduction
  • Dose‐Response Curves
  • Receptor Theory
  • Conclusions
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

   Arunlakshana, O. and Schild, H.O. 1959. Some quantitative uses of drug antagonists. Br. J. Pharmacol. 14:48‐58.
   Black, J.W. and Leff, P. 1983. Operational models of pharmacological agonist. Proc. R. Soc. London B Biol. Sci. 220:141‐162.
   Christopoulos, A. and Kenakin, T. 2002. G protein–coupled receptor allosterism and complexing. Pharmacol. Rev. 54:323‐374.
   Furchgott, R.F. 1966. The use of β‐haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor‐agonist complexes. In Advances in Drug Research, Vol. 3 (N.J. Harper and A.B. Simmonds, eds.) pp. 21‐55. Academic Press, San Diego.
   Furchgott, R.F. 1972. The classification of adrenoceptors (adrenergic receptors): An evaluation from the standpoint of receptor theory. In Handbook of Experimental Pharmacology, Catecholamines, Vol. 33 (H. Blaschko and E. Muscholl, eds.) pp. 283‐335. Springer‐Verlag, New York and Heidelberg.
   Gaddum, J.H. 1937. The quantitative effects of antagonistic drugs. J. Physiol. 89:7P‐9P.
   Gaddum, J.H., Hameed, K.A., Hathway, D.E., and Stephens, F.F. 1955. Quantitative studies of antagonists for 5‐hydroxytryptamine. Q. J. Exp. Physiol. 40:49‐74.
   Jakubic, J., Bacakova, L., Lisa, V., El‐Fakahany, E.E., and Tucek, S. 1997. Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors Mol. Pharmacol. 52, pp. 172‐179.
   Kaumann, A.J. and Marano, M. 1982. On equilibrium dissociation constants for complexes of drug‐receptor subtypes: Selective and non‐selective interactions of partial agonists with two plausible β‐adrenoceptor subtypes mediating positive chronotropic effects of (β)‐isoprenaline in kitten atria. Naunyn‐Schmiedebergs Arch. Pharmacol. 318:192‐201.
   Kenakin, T.P. 1980. Effects of equilibration time on the attainment of equilibrium between antagonists and drug receptors. Eur. J. Pharmacol. 66:295‐306.
   Kenakin, T.P. 1982. The Schild regression in the process of receptor classification. Can. J. Physiol. Pharmacol. 60:249‐265.
   Kenakin, T.P. 1985a. Prenalterol as a selective cardiostimulant: Differences between organ and receptor selectivity. J. Cardiovasc. Pharmacol. 7:208‐210.
   Kenakin, T.P. 1985b. Schild regressions as indicators of non equilibrium steady states and heterogeneous receptor populations. Trends Pharmacol. Sci. 6:68‐71.
   Kenakin, T.P. 1987. What can we learn from models of complex drug antagonism in classifying hormone receptors? In Receptor Biochemistry and Methodology, Vol. 6: Perspectives on Receptor Classification ( J.W. Black, D.H. Jenkinson, and V.P. Gerskowitch, eds.) pp. 169‐184. Alan R. Liss, New York.
   Kenakin, T.P. 1992. Tissue response as a functional discriminator of receptor heterogeneity: The effects of mixed receptor populations on Schild regressions. Mol. Pharmacol. 41:699‐707.
   Kenakin, T.P. and Beek, D. 1987. The effects of Schild regressions of antagonist removal from the receptor compartment by a saturable process. Naunyn Schmiedebergs Arch. Pharmacol. 385:103‐108.
   Kenakin, T.P., Jenkinson, S., and Watson, C. 2006. Determining the potency and molecular mechanism of action of insurmountable antagonists. J. Pharmacol. Exp. Ther. 319;710‐723.
   Krebs, H.A. 1950. Body size and tissue respiration. Biochim. Biophys. Acta 4:249‐269.
   Krebs, H.A. and Henseleit, K. 1932. Untersuchungen über die Harnstoffbildung im Tierkorper. Z. Physiol. Chem. 210:33‐66.
   MacKay, D. 1966. A new method for the analysis of drug‐receptor interactions. In Advances in Drug Research, Vol. 3 (N.J. Harper and A.B. Simmonds, eds.) pp. 1‐19. Academic Press, San Diego.
   MacKay, D. 1978. How should values of pA2 and affinity constants for pharmacological competitive antagonists be estimated? J. Pharm. Pharmacol. 30:312‐313.
   Parascandola, J. 1986. The development of receptor theory. In Pharmacological Methods, Receptors and Chemotherapy, Vol. 3 (M.J. Parnham and J. Bruinvels, eds.) pp. 129‐158. Elsevier/North‐Holland, Amsterdam.
   Paton, W. D. M. and Rang, H. P. 1965. The uptake of atropine and related drugs by intestinal smooth muscle of the guinea pig in relation to acetylcholine receptors. Proc. R. Soc. Lond. [Biol.] 163:1‐44.
   Schild, H.O. 1949. pAx and competitive drug antagonism. Br. J. Pharmacol. 4:277‐280.
   Stephenson, R.P. 1956. A modification of receptor theory. Br. J. Pharmacol. 11:379‐393.
   Tyrode, M.V. 1910. Mode of action of some purgative salts. Arch. Int. Pharmacodyn. Ther. 20:205‐210.
Key References
   Furchgott, 1972. See above.
  Discusses very important concepts in isolated tissue methods with respect to the use of techniques described in this unit.
   Kenakin, T.P. 2006. A Pharmacology Primer: Theory, Application and Methods, 2nd ed. Academic Press/Elsevier, Amsterdam.
  A survey of methods and procedures for measuring drug activity in isolated tissues.
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