GPCR Drug Discovery: Emerging Targets, Novel Approaches and Future Trends

Abstract

G-protein coupled receptors (GPCRs) are a class of seven-transmembrane proteins that have attracted tremendous interest in both the pharmaceutical industry and academia for decades owing to their physiological and therapeutical importance and accessibility for small molecule drug discovery. GPCRs play critical roles in physiological responses to a variety of stimuli such as ions, small molecules, macromolecules, peptides and other proteins, which are associated with the vast biological functions mediated by GPCRs. Aspects of cognition, immune response, and cellular organization as well as many others, are regulated by GPCR signaling. The pharmacological regulation of GPCRs provides leverage for the treatment of various human diseases including those of the central nervous system (CNS), cancer, viral infections, inflammatory disorders, metabolic disorders, and others. Moreover, the location of GPCRs in the cellular membrane allows unique pharmacological access to these proteins while the effectors and second messenger systems coupled to the receptors allow for efficient drug action and drug targeting in the discovery of novel therapeutics. Intriguingly, GPCRs represent the largest family of druggable proteins in the human genome and unsurprisingly are targeted by more than 30% of marketed drugs worldwide. This issue contains a diverse collection of reviews covering the cutting-edge biology and medicinal chemistry in GPCR drug discovery, with special attention to new approaches in traditional targets, emerging targets, and future trends. As a traditional drug target, the dopamine D1 receptor (D1R) is essential to neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Recent chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also holds promise for creating pharmacotherapy for several neurological diseases. Allen and colleagues provide an overview of the major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators, highlighting their structure activity relationships and medicinal chemistry [1]. An impaired signaling capacity of the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R), another traditional drug target in class A GPCRs, contributes to the