G-protein coupled receptors (GPCRs) are ubiquitous. Their role in communicating extracellular events across the cell membrane is essential and has not been overlooked by those interested in the processes of signal transduction and by those attracted to manipulating signal pathways for disease therapy. The nature of GPCRs makes them suitable targets fordrug therapy foranumber ofreasons. Depending on the signal pathway and the desired physiological response, they can be activated (agonists) or blocked (antagonists). The ligand binding site is accessible from the extracellular environment, thereby not requiring drugs to be able to enter the cell. Receptor subtype homology enables the development of ligands having a balanced effect by interacting equally with each subtype. In addition, receptor subtype heterology holds promise for the ability to exquisitely tune ligand specificity for particular tissues and particular physiological responses. During the last 5 years or so, there have been significant advances in our understanding of the details of the manner in which hormones such as angiotensin II and epinephrine bind to GPCRs. The liaison between molecular biology and medicinal chemistry in this area has given birth to the concept of a ligand binding site, which is conserved among a great number of GPCRs and can be used by antagonists to block the effects of the endogenous agonist. In addition, we are beginning to understand the biochemical processes involved with agonist activation, signal transduction, constitutive activity, and so forth. How
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