Editorial [Hot Topic: G-Protein-Coupled Receptors (GPCRs) and Drug Discovery (Guest Editor: Luca Gentilucci)]

G-protein coupled receptors (GPCR) are involved in a large variety of physiological and pathophysiological processes. Their fundamental role is highlighted by the fact that of the around 500 currently marketed drugs, more than 30% are GPCR modulators. GPCR agonist and antagonist drugs have therapeutic benefit across a broad spectrum of diseases, including pain (opioid receptor agonists), asthma ( β2-adrenoceptor agonists), peptic ulcers (histamine H2 receptor antagonists), migraine (serotonin 5-HT1B/1D agonists), hypertension (angiotensin AT2 receptor antagonists), schizophrenia (serotonin 5-HT2 receptor agonists and dopamine receptor antagonists), rhinitis or allergy (histamine H1 receptor and chemokine receptor antagonists), etc. Besides, no single class of proteins ranks higher than GPCRs in terms of new drug discovery potential. It has been estimated that of the around 400 GPCRs considered to be potential drug targets, only ∼30 are targeted by currently marketed drugs. The natural ligand has been identified for a further 210 receptors, which leaves around 160 orphan receptors with no known ligand or function. Without any doubt, therapeutic intervention at these novel receptors will have major benefit in a wide range of human diseases. The matter has been made more complicated by the fact that several GPCR ligands do not interact at the natural ligand binding site, rather such compounds interact elsewhere on the receptor to modulate its activity (allosteric sites). Thus, there may be many as yet uncharacterized drug binding sites within the GPCR that could be exploited for therapeutic intervention. In addition, the recent realization that these receptors form homo-oligomeric and hetero-oligomeric complexes has added a new dimension to rational drug design. GPCRs can be classified into three major families according to sequence homology. Family A is the largest subgroup and includes catecholamine, neuropeptide, chemokine, glycoprotein, lipid and nucleotide receptors. Family B contains receptors for a large number of peptides such as calcitonin gene-related peptide (CGRP) and calcitonin. Family C contains the metabotropic glutamate receptors (mGluRs), γ-amino butyric acid (GABAB) receptors and the calcium-sensing receptor (CaR). Apparently, the large super-family of GPCRs is correlated to a wide range of structurally diverse, heterogeneous ligands. For this reason, a systematic review of the topic is of little utility. Rather, this issue of Current Drug Targets deals with some selected aspects of the current status and future directions of GPCRs investigation, with a particular emphasis on their potential impact on medicinal chemistry. In their review, P. M. Sexton and co. exhaustively discuss the recently de-orphanised relaxin receptors and related ligands. Relaxins (H1, H2 and H3), belong to a peptide family which comprises also insulin, insulin-like peptides (INSL3-6), and insulin-like growth factors (IGF I-II). The relaxin/INSL receptor system is a promising candidates for treatments of problems associated with pregnancy, but also as contraceptive agents, for the treatment of fibrosis, cardiac failure and asthma. The review of P. A. Keller and co. addresses the strategies and the obstacles that have arisen in the search of Corticotrophin Releasing Hormone-based agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimer's, pain and the prevention of premature birth. The pharmacology of Nociceptin/Orphanin FQ peptide receptors has been the subject of a couple of articles. In the first one, L.- C. Chiou and co. describe the different kinds of NOP receptor agonists and antagonists, and their possible clinical indications: agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, etc. while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. In the second one, S. Spampinato and co. discuss the efficacy of NOP receptor agonists to induce receptor endocytosis. Prolonged receptor signaling mediated by receptor endocytosis and recycling/reactivation might reduce the development of tolerance but can enhance compensatory mechanisms that lead to supersensitivity of specific signaling pathways. In the following review, F. Nyberg and M. Hallberg investigate the fate of neuropeptides after receptor stimulation. There is increasing evidence that, besides to peptide inactivation by enzymatic degradation, in many cases the active neuropeptides are enzymatically converted to products that modulate the action of their parent compounds. The contribution of D.R. Herr and J. Chun concerns of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two lysophospholipids that mediate a diverse range of biological processes......