The measurement of receptor signaling bias

Abstract

This chapter describes a method to quantify biased signaling effects of agonists; this approach can furnish a scale for medicinal chemists to optimize biased profiles. Biased ligands have different pharmacological properties on a molecular level (stabilization of different receptor active states) and thus can have different pharmacological profiles therapeutically. The calculation of transduction ratios (ΔΔlog(τ/KA)) values (where τ is efficacy and KA a measure of affinity) allows the identification of agonists that demonstrate unique signaling either for different signaling pathways linked to the receptor, differences in cellular host, effects of receptor mutation, or receptor selectivity profiles. The procedure includes statistical methods to assess the significance of these effects.