Ligand-Binding Kinetics on Histamine Receptors

Equilibrium-binding affinities of ligands for a drug target do not always accurately reflect the success of drug candidates in the clinic. Affinity-based predictions concerning competitive antagonism on the target will only be accurate if equilibrium binding of both ligands is allowed. Unless equilibrium for ligand bind- ing is obtained really quickly, it is unlikely that equilibrium is established in vivo. Instead, concentrations of (endogenous) ligands rapidly fluctuate over time. Hence, the velocity in which binding equilibrium is reached and the duration of target occupancy by the ligand (also known as residence time) are thought to be more important predictors of drug in vivo efficacy. This chapter provides the theoretical background on ligand-binding kinetics and several experimental approaches to determine the target residence time of antihistamines on histamine receptors.