G protein-coupled receptor (GPCR)-dependent transduction

Many current pharmaceutical therapies target G protein-coupled receptors (GPCRs), with some of their side-effect profiles attributable to the offtarget binding. Allosteric modulators are ligands that bind to a secondary or allosteric site on a receptor and regulate the pharmacological actions of a ligand bound to the orthosteric site. The allosteric site is spatially distinct from the orthosteric site, subunit-specific, and saturable; thus, allosteric modulators have increased binding specificity and an effect ceiling. Allosteric modulators are classified by their cooperativity with the orthosteric ligand, with positive allosteric modulators (PAMs) displaying positive cooperativity, negative allosteric modulators (NAMs) displaying negative cooperativity, and neutral allosteric modulators (NALs) displaying neutral cooperativity. Notably, PAMs, NAMs, and NALs lack intrinsic activity; however, ago-PAMs and bitopic ligands can exert a pharmacological action without the presence of an orthosteric ligand. Biased signaling occurs when a ligand preferentially signals through a specific intracellular pathway. Some allosteric modulators display biased effects applicable in pharmaceuticals aiming to mitigate the effects of detrimental intracellular signaling pathways. GPCR allostery combined with biased signaling represents a potential means for novel pharmaceuticals with negligible side effects. This chapter will describe our current understanding of GPCR allosteric modulation with an emphasis on biased signaling and an eye to the future of research in this field.