10 - Agonist activation and analysis

Summary

This chapter covers the quantitative aspect of agonist activation: how the blood, and by extension the interstitial fluid, presents a pharmaceutical agent to the cell; quantification of drug concentration and tissue response; diffusion and elimination of an intracellular agent; statistical analysis of the tissue response; and the difficult problems associated with drug development. Because of the necessary role played by agonist receptors in this process, the background of some of the major receptor types is also included.

Membrane receptor proteins

Agonists initiate a cell response by binding to a receptor. Without trying to give a complete list of every kind of receptor, three of the major categories of receptors are the G-protein coupled receptors (GPCRs), the tyrosine kinase receptors, and nuclear receptors. GPCRs dominate cell activation using the temporally limited G-protein system. There are more than 800 GPCR proteins, and the complexity of their activation scheme is daunting. Tyrosine kinase receptors are activated by insulin and a variety of growth factors, and activate processes associated with the structural growth of cells and tissues. Nuclear receptors bind to hydrophobic hormones, steroids, thyroid hormones, etc., that do their work by initiating gene transcription. This section gives a brief overview of these receptor types, with the understanding that all of them have far more complexity than can be covered here. Recognizing the pivotal role these molecules play in linking the quantitative aspects of cell activation, pharmacokinetics, dose–response relations, intracellular diffusion, and data analysis of biological responses, it is appropriate that a general discussion of their functions is included.