Allosteric Drugs and Seven Transmembrane Receptors

Terry      Kenakin

Abstract

Seven transmembrane Receptors (7TMRs) transmit signals through changes in conformation; the binding of ligands to any site on the receptor has the potential to change the receptor conformation. Allosteric ligands are defined as those which bind to sites other than the one needed for the endogenous receptor agonist (neurotransmitters, hormones). Allosteric ligand function is saturable (comes to a finite magnitude when the allosteric site is fully occupied) and probe dependent (the effects vary with different co-binding ligands). Both direct effects on receptor conformation and the induced effect on endogenous ligands must be considered when describing allosteric ligands; this paper will describe the quantitative models available to characterize these allosteric effects in molecular terms which can then be used to predict allosteric effects in all systems.

Keywords: Allosteric modulation, allosteric antagonism, biased agonism, drug discovery, positive allosteric modulation efficacy, receptor theory

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