Introduction

G protein-coupled receptors (GPCRs) are the most-targeted class of protein for novel and approved drugs. Nearly 50% of all drugs presently sold on the global market target a GPCR and GPCR-targeted therapeutics represent approximately 34% of all drugs that have been approved by the Food and Drug Administration. There are thought to be 108 members of the GPCR family with a wide variety of endogenous ligands, signaling activities, and patterns of tissue expression; yet all GPCRs share several common structural features including seven transmembrane α-helices, an extracellular N-terminus, an intracellular C-terminus, and the ability to couple with and signal via guanine nucleotide binding proteins (G proteins). Historically, GPCRs were thought to propagate their signal from the extracellular environment into the cell through the binding of a ligand agonist to the orthosteric (i.e., primary) receptor site and the consequent conformational change of that receptor which allowed for G protein activation. More recently, it has become apparent that the activity of GPCRs is fine-tuned and controlled by a wide array of signaling partners that bind allosteric (i.e., "‘other”) receptor sites. Novel and precise regulation of GPCRs stemming from allosteric sites may lead to the development of improved drugs targeting a protein family with an already successful history of drug development. The purpose of this chapter is to summarize some leading areas of research in allosteric modulation of GPCRs where knowledge gaps have, or are, actively being addressed. Each of these areas will then be elaborated on in their own subsequent chapters. The research described herein focuses on preclinical evaluation of allostery for GPCRs with an emphasis on core and emerging concepts in pharmacology, biochemistry, and medicinal chemistry.