Heptahelical G protein-coupled receptors (GPCR) currently represent perhaps the most important pharmacotherapeutic target. Nearly 50% of existing licensed therapeutic compounds functionally interact with GPCRs in an agonistic (stimulatory) or antagonistic (inhibitory) manner. This limiting and rigid pharmacological appreciation of GPCR-based therapeutics possessing either agonistic or antagonistic activity has stood for nearly three decades. However our understanding of the true physico-chemical nature of the drug-responsive GPCR has expanded dramatically, introducing many new concepts that force a realignment of our views of drug classification and concepts of efficacy. With advances in protein-complex purification and analysis it is now clear that the functional entity that creates the drug-receptive GPCR is comprised of the GPCR core plus many additional co-factor proteins that profoundly ‘condition’ the output receptor signals. In addition to these co-factor proteins affecting downstream signaling they also affect the structural conformation of the extracellular regions of the receptor, thus also controlling ligand interaction choices. These distinct GPCR-containing structures are typically referred to as receptorsomes and their complexity and stoichiometry are likely affected by specific tissues expression, disease state or physiological age of the organism. The activity of many previously developed drugs now appears to be mediated through selective activation of specific subsets of these receptorsomes. The distinction of the protein co-factors in these diverse receptorsomes allows them to selectively interact with pre-assembled signaling complexes that allow a firm connection between downstream signal and receptorsome type. Therefore with the appropriate application of this knowledge it may be possible to develop therapeutic compounds that selectively interact with specific receptorsomes to engender a ‘cleaner’ and more specific signaling effect. Such signal-selective compounds are often referred to as ‘biased agonists’. Many currently existing classical receptor antagonists are in fact signal-selective biased agonistic agents that were previously overlooked due to their distinct signaling activity compared to classical agonists. Future development of GPCR-targeted biased agonistic agents may create drugs that possess a more specific efficacy and therefore avoid deleterious off-target actions or drug contraindications. This special research topic will compile and analyze both the most exciting and up-to-date developments of this important new class of therapeutic agents as well as document the novel breakthroughs in receptor signaling theory associated with controlled GPCR signaling diversity. The research topic will be of tremendous interest to molecular endocrinologists, medicinal chemists, pharmacologists, pharamacokineticists, bioinformaticians, molecular biologists and drug developers. The topic will cover the description of biased agonism receptor formats, the synthesis and development of the biased agonists themselves, the discovery of biased agonism as a concept and the development and targeting of biased agonism for physiological therapies.
Heptahelical G protein-coupled receptors (GPCR) currently represent perhaps the most important pharmacotherapeutic target. Nearly 50% of existing licensed therapeutic compounds functionally interact with GPCRs in an agonistic (stimulatory) or antagonistic (inhibitory) manner. This limiting and rigid pharmacological appreciation of GPCR-based therapeutics possessing either agonistic or antagonistic activity has stood for nearly three decades. However our understanding of the true physico-chemical nature of the drug-responsive GPCR has expanded dramatically, introducing many new concepts that force a realignment of our views of drug classification and concepts of efficacy. With advances in protein-complex purification and analysis it is now clear that the functional entity that creates the drug-receptive GPCR is comprised of the GPCR core plus many additional co-factor proteins that profoundly ‘condition’ the output receptor signals. In addition to these co-factor proteins affecting downstream signaling they also affect the structural conformation of the extracellular regions of the receptor, thus also controlling ligand interaction choices. These distinct GPCR-containing structures are typically referred to as receptorsomes and their complexity and stoichiometry are likely affected by specific tissues expression, disease state or physiological age of the organism. The activity of many previously developed drugs now appears to be mediated through selective activation of specific subsets of these receptorsomes. The distinction of the protein co-factors in these diverse receptorsomes allows them to selectively interact with pre-assembled signaling complexes that allow a firm connection between downstream signal and receptorsome type. Therefore with the appropriate application of this knowledge it may be possible to develop therapeutic compounds that selectively interact with specific receptorsomes to engender a ‘cleaner’ and more specific signaling effect. Such signal-selective compounds are often referred to as ‘biased agonists’. Many currently existing classical receptor antagonists are in fact signal-selective biased agonistic agents that were previously overlooked due to their distinct signaling activity compared to classical agonists. Future development of GPCR-targeted biased agonistic agents may create drugs that possess a more specific efficacy and therefore avoid deleterious off-target actions or drug contraindications. This special research topic will compile and analyze both the most exciting and up-to-date developments of this important new class of therapeutic agents as well as document the novel breakthroughs in receptor signaling theory associated with controlled GPCR signaling diversity. The research topic will be of tremendous interest to molecular endocrinologists, medicinal chemists, pharmacologists, pharamacokineticists, bioinformaticians, molecular biologists and drug developers. The topic will cover the description of biased agonism receptor formats, the synthesis and development of the biased agonists themselves, the discovery of biased agonism as a concept and the development and targeting of biased agonism for physiological therapies.
