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Molecular Pharmacology, Vol 15, 60-70, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Multi-subsite Receptors for Multivalent Ligands

Application to Drugs, Hormones, and Neurotransmitters

ANDRE DE LEAN 1, PETER J. MUNSON 1, and DAVID RODBARD 1

1 Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014

Detailed structure-activity relationships of many drugs and hormones indicate that ligand-receptor binding involves the interaction of several functional regions on the ligand with complementary receptor "subsites." However most hormone receptor binding models have been based on a simple bimolecular reaction obeying the mass action law. We present a quantitative reinterpretation in pharmacological terms of the theory of flexible polyvalent ligand binding. The model explains: 1) the occurrence of complex binding isotherms showing both apparent heterogeneous and cooperative binding sites; 2) bell-shaped dose response curves; 3) the properties of full and partial agonists; 4) how a given antagonist can be either "competitive" or "noncompetitive" depending on concentration used. The classical simple bimolecular interaction between drug and receptor is a limiting case of the model, when steric hindrance completely prevents multiple receptor occupancy, or when the ligand and the receptor interact in an all-or-none mode.

Note:
ACKNOWLEDGMENTS Charles De Lisi kindly reviewed the manuscript and provided many helpful suggestions. The numerical analysis was based in part on the methods of Feldman (39).

Submitted on April 28, 1978
Accepted on August 7, 1978




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