G-protein-coupled receptor pharmacology: examining the edges between theory and proof

Over the past year, several salubrious concepts in the field of G-protein-coupled receptors (GPCRs) have been brought to the forefront of GPCR research, and theoretical models that describe their activation continue to be amended to accommodate new experimental data. Pharmacologists have traditionally divided ligands into agonists, which stimulate receptors, and antagonists, which block receptor activation. More recently, however, scientists have come to realize that GPCRs can also exhibit basal activity, and with this knowledge they have come to the understanding that many drugs previously classified as neutral antagonists, actually demonstrate 'negative efficacies'. Given the breadth of the subject matter, and the large number of publications on GPCRs produced each year, this review will highlight only the following topics: (i) allosteric modulators of GPCRs; (ii) functional selectivity and its relationship to drug efficacy; (iii) the prominence of inverse agonists as therapeutics; and (iv) new technologies that are being introduced that may allow us to better understand the 'when and how' of GPCR signaling.