ABSTRACT: Peptide-liganded G protein-coupled receptors (GPCRs) are a growing fraction of GPCR drug targets, concentrated in two of the five major GPCR structural classes. The basic physiology and pharmacology of some within the rhodopsin class, for example, the enkephalin (μ opioid receptor, MOR) and angiotensin (ATR) receptors, and most in class B, all the members of which are peptide receptors, are well-known, whereas others are less so. Furthermore, with the notable exception of opioid peptide receptors, the ability to translate from peptide to "drug-like" (i.e., low-molecular-weight nonpeptide) molecules, with desirable oral absorption, brain penetrance, and serum stability, has met with limited success. Yet, peripheral peptide administration in patients with metabolic disorders is clinically effective, suggesting that "drug-like" molecules for peptide receptor targets may not always be required for disease intervention. Here, we consider recent developments in GPCR structure analysis, intracellular signaling, and genetic analysis of peptide and peptide receptor knockout phenotypes in animal models. These lines of research converge on a better understanding of how peptides facilitate adaptive behaviors in mammals. They suggest pathways to translate this burgeoning information into identified drug targets for neurological and psychiatric illnesses such as obesity, addiction, anxiety disorders, and neurodegenerative diseases. Advances centered on the peptide ligands oxytocin, vasopressin, GLP-1, ghrelin, PACAP, NPY, and their GPCRs are considered here. These represent the spectrum of progress across the "virtual pipeline", of peptide receptors associated with many established drugs, those of long-standing interest for which clinical application is still under development, and those just coming into focus through basic research.
