The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the apelin receptor, including apelin-17, apelin-13, and [Pyr 1 ]apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the apelin receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the apelin receptor and are blocked by apelin receptor antagonists. This review summarizes the pharmacology of these ligands and the apelin receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the apelin receptor protein. 468 Read et al. Receptor residues implicated in apelin binding by mutagenesis. b Receptor residues affecting bias and internalization by mutagenesis. 470 Read et al.

Chronic kidney disease (CKD) is an increasingly common public health concern with a global prevalence of ~10% 1 . This disease now ranks as the 12th leading cause of death worldwide 1 . CKD results from a heterogeneous group of conditions that lead to a progressive and irreversible impairment in kidney function. It is defined as a reduction in estimated glomerular filtration rate (eGFR) to <60 ml/min/1.73 m 2 and/or the presence of markers of kidney damage on at least two occasions at least 3 months apart 2 .CKD is independently associated with cardiovascular disease 3 . As eGFR decreases, the risks of major cardiovascular events, cardiovascular mortality and all-cause mortality increase 4 . Importantly, patients with stage 1-3 CKD (eGFR >30 ml/min/1.73 m 2 ) are more likely to die from cardiovascular disease than they are to reach kidney failure 4,5 and around 50% of patients with kidney failure die from cardiovascular causes 6 . Not only are cardio vascular events more common in patients with CKD, but outcomes following such events are worse than in the general population 7 . Almost 8% of global cardiovascular deaths in 2017 were attributable to CKD 1 .Hypertension is both a cause and a consequence of CKD. As kidney function declines, blood pressure rises, and more than 85% of patients with CKD are hypertensive 8 . Thus, reducing blood pressure in CKD is a key therapeutic strategy that not only slows the progression to kidney failure but also reduces cardiovascular risk 9 . However, more than 30% of patients with CKD require four or more antihypertensive agents to achieve adequate blood pressure control and up to 50% never reach their target blood pressure 8 . Uncontrolled hypertension promotes the development of left ventricular hypertrophy (LVH). The prevalence of LVH increases as kidney function declines and it is present in ~50% of patients with an eGFR of <25 ml/min/1.73 m 2 (ref. 10 ). Alongside hypertension and LVH, arterial stiffness, endothelial dysfunction and proteinuria are characteristic features of CKD and important independent predictors of cardiovascular disease 4,[11][12][13][14] .Current evidence-based management of CKD is limited to blockers of the renin-angiotensin-aldosterone system (RAAS) that slow CKD progression 4,8 . Sodiumglucose co-transporter 2 (SGLT2) inhibitors, which were originally developed for the treatment of type 2 diabetes mellitus (T2DM), have also now been shown to improve kidney and cardiovascular end points in patients with and without T2DM 15,16 . However, an urgent unmet need remains for novel treatments 17 . The ideal therapy would provide direct renoprotection and reduce proteinuria, while also offering broad cardiovascular protection. The apelin system has exciting therapeutic potential in this regard. In this Review, we focus on current

The apelin receptor is a potential target in the treatment of heart failure and pulmonary arterial hypertension where levels of endogenous apelin peptides are reduced but significant receptor levels remain. Our aim was to characterise the pharmacology of a modified peptide agonist, MM202, designed to have high affinity for the apelin receptor and resistance to peptidase degradation and linked to an anti-serum albumin domain antibody (AlbudAb) to extend half-life in the blood. In competition, binding experiments in human heart MM202-AlbudAb (pK i = 9.39 ± 0.09) bound with similar high affinity as the endogenous peptides [Pyr 1 ]apelin-13 (pK i = 8.83 ± 0.06) and apelin-17 (pK i = 9.57 ± 0.08). [Pyr 1 ]apelin-13 was tenfold more potent in the cAMP (pD 2 = 9.52 ± 0.05) compared to the β-arrestin (pD 2 = 8.53 ± 0.03) assay, whereas apelin-17 (pD 2 = 10.31 ± 0.28; pD 2 = 10.15 ± 0.13, respectively) and MM202-AlbudAb (pD 2 = 9.15 ± 0.12; pD 2 = 9.26 ± 0.03, respectively) were equipotent in both assays, with MM202-AlbudAb tenfold less potent than apelin-17. MM202-AlbudAb bound to immobilised human serum albumin with high affinity (pK D = 9.02). In anaesthetised, male Sprague Dawley rats, MM202-AlbudAb (5 nmol, n = 15) significantly reduced left ventricular systolic pressure by 6.61 ± 1.46 mm Hg and systolic arterial pressure by 14.12 ± 3.35 mm Hg and significantly increased cardiac contractility by 533 ± 170 mm Hg/s, cardiac output by 1277 ± 190 RVU/min, stroke volume by 3.09 ± 0.47 RVU and heart rate by