Moving from cells to animals: Challenges of studying allosteric modulators in vivo

A pure allosteric modulator is a compound that tweaks the activity of its target receptor without directly activating or inactivating that receptor. In theory, allosteric modulators were meant to be a pharmacological means of only altering deviant GPCR activity. The detection of allosteric effects in vivo is substantially more challenging than drug development for orthosteric ligands. The development of a novel chemical entity into a clinically useful drug is challenging for “standard” therapeutics whose mechanisms of action are well-characterized and understood. In this chapter we will explore some exemplary cases of preclinical allosteric modulator evaluation in vivo; some of which are successes and others are not, but all of which provide valuable information on challenges that must be overcome to assess allosteric ligands in vivo. We will investigate some of the progress to date for GPCR allosteric modulator testing in vivo and consider hurdles, and the means for overcoming these hurdles, as we seek to translate biochemical findings to whole organism effects.