Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [197], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [153]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GPR65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [65, 66]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [30]. PG 99-465 [117] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [36]. The selective PAC1 receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP or the PACAP peptides [118]. Two deletion variants of maxadilan, M65 [183] and Max.d.4 [119] have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised.

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [161], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [121]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GPR65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [194], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [150]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3 GPR4 GPR6 GPR12 GPR15 GPR17 GPR20 GPR22 GPR26 GPR31 GPR34 GPR35 GPR37 GPR39 GPR50 GPR63 GRP65 GPR68 GPR75 GPR84 GPR87 GPR88 GPR132 GPR149 GPR161 GPR183 LGR4 LGR5 LGR6 MAS1 MRGPRD MRGPRX1 MRGPRX2 P2RY10 TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

BACKGROUND AND PURPOSE An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. EXPERIMENTAL APPROACH Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment. KEY RESULTS We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi-drug treatments with high efficacy and minimal off-target effects. CONCLUSION AND IMPLICATIONS We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses.

Background: Diurnal variations in the incidence of events such as heart attack and stroke suggest a role for circadian rhythms in the etiology of cardiovascular disease. The aim of this study was to assess the influence of the suprachiasmatic nucleus (SCN) circadian clock on cardiovascular function. Methodology/Principal Findings: Heart rate (HR), blood pressure (BP) and locomotor activity (LA) were measured in circadian mutant (Vipr2) mice and wild type littermates, using implanted radio-telemetry devices. Sleep and wakefulness were studied in similar mice implanted with electroencephalograph (EEG) electrodes. There was less diurnal variation in the frequency and duration of bouts of rest/activity and sleep/wake in Vipr2 mice than in wild type (WT) and short ‘‘ultradian’’ episodes of arousal were more prominent, especially in constant conditions (DD). Activity was an important determinant of circadian variation in BP and HR in animals of both genotypes; altered timing of episodes of activity and rest (as well as sleep and wakefulness) across the day accounted for most of the difference between Vipr2 mice and WT. However, there was also a modest circadian rhythm of resting HR and BP that was independent of LA. Conclusions/Significance: If appropriate methods of analysis are used that take into account sleep and locomotor activity level, mice are a good model for understanding the contribution of circadian timing to cardiovascular function. Future studies of the influence of sleep and wakefulness on cardiovascular physiology may help to explain accumulating evidence linking disrupted sleep with cardiovascular disease in man. Citation: Sheward WJ, Naylor E, Knowles-Barley S, Armstrong JD, Brooker GA, et al. (2010) Circadian Control of Mouse Heart Rate and Blood Pressure by the Suprachiasmatic Nuclei: Behavioral Effects Are More Significant than Direct Outputs. PLoS ONE 5(3): e9783. doi:10.1371/journal.pone.0009783 Editor: Shin Yamazaki, Vanderbilt University, United States of America Received September 11, 2009; Accepted February 25, 2010; Published March 22, 2010 Copyright: 2010 Sheward et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Medical Research Council (G9719726) and the Wellcome Trust. The authors also acknowledge the support of the British Heart Foundation Centre of Research Excellence Award RE/08/001. E.N. was supported by National Institutes of Health (NIH) training grant T32 AG02050602 and S.K.-B. by the EPSRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: tony.harmar@ed.ac.uk

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Ligand-gated ion channels are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA(1) (GPR81) with lactate, HCA(2) (GPR109A) with 3-hydroxybutyric acid, HCA(3) (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA(4) (GPR23), LPA(5) (GPR92), LPA(6) (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org).

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Most medicines are chemical substances that work by interacting with specific target proteins in the body. The International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS) have joined forces to develop the Guide to PHARMACOLOGY (www.guidetopharmacology.org), a portal to information on the targets of licensed drugs and other targets of current research interest, such as those linked to human disease. Over the next 3 years, with support from the Wellcome Trust, IUPHAR and BPS, the Guide to PHARMACOLOGY portal will be expanded to cover all the targets of current licensed drugs and those with potential to be targets of future therapeutics. Our goal is to provide scientists, doctors, allied professions and the general public with a ‘one-stop shop’ source of information on how drugs work, and to help researchers to design experiments using the appropriate reagents.

The International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to PHARMACOLOGY (http://www.guidetopharmacology.org) is a new open access resource providing pharmacological, chemical, genetic, functional and pathophysiological data on the targets of approved and experimental drugs. Created under the auspices of the IUPHAR and the BPS, the portal provides concise, peer-reviewed overviews of the key properties of a wide range of established and potential drug targets, with in-depth information for a subset of important targets. The resource is the result of curation and integration of data from the IUPHAR Database (IUPHAR-DB) and the published BPS ‘Guide to Receptors and Channels’ (GRAC) compendium. The data are derived from a global network of expert contributors, and the information is extensively linked to relevant databases, including ChEMBL, DrugBank, Ensembl, PubChem, UniProt and PubMed. Each of the ∼6000 small molecule and peptide ligands is annotated with manually curated 2D chemical structures or amino acid sequences, nomenclature and database links. Future expansion of the resource will complete the coverage of all the targets of currently approved drugs and future candidate targets, alongside educational resources to guide scientists and students in pharmacological principles and techniques.

The award of the 2012 Nobel Prize in Chemistry to Robert Lefkowitz and Brian Kobilka for their work on the structure and function of GPCRs, spanning a period of more than 20 years from the cloning of the human β2‐adrenoceptor to determining the crystal structure of the same protein, has earned both researchers a much deserved place in the pantheon of major scientific discoveries. GPCRs comprise one of the largest families of proteins, controlling many major physiological processes and have been a major focus of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR) since its inception in 1987. We report here recent efforts by the British Pharmacological Society and NC‐IUPHAR to define the endogenous ligands of ‘orphan’ GPCRs and to place authoritative and accessible information about these crucial therapeutic targets online.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase‐activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon‐like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone‐releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs – PAC1, VPAC1 and VPAC2– belonging to class B (also referred to as class II, or secretin receptor‐like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin‐releasing factor, calcitonin and related peptides. PAC1 receptors are selective for PACAP, whereas VPAC1 and VPAC2 respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC2 receptor in susceptibility to schizophrenia and the PAC1 receptor in post‐traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co‐transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (http://www.iuphar‐db.org/DATABASE/FamilyMenuForward?familyId=67).LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein‐Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue‐1

The contraction of the pharmaceutical industry has resulted in the underuse of a great deal of human capital and brainpower. This editorial appeals to pharmacologists who may be currently underemployed to volunteer their skills by contributing to the British Pharmacological Society's (BPS) Guide to Receptors and Channels (GRAC), and the NC-IUPHAR database (IUPHAR-DB). NC-IUPHAR has 60 subcommittees on specialized pharmacological areas where scientists freely give their time for articles on receptors or channels, and to populate IUPHAR-DB. These are freely available to all on the Web via a new resource: http://www.guidetopharmacology.org. The site features articles on all aspects of pharmacology, particularly new areas: microRNAs, epigenetics and transporters. One aspect that would be covered, alongside nomenclature and key pharmacology, is the drug discovery challenges in each area. Here the knowledge base from the pharmaceutical industry would be particularly valuable. In a separate editorial, Anne Hayes and Jackie Hunter discuss the scientific fallout from the recent contraction of the pharmaceutical industry, intended to stimulate further discussion concerning the best way to achieve the publication of negative data in drug discovery research: http://dx.doi.org/10.1111/j.1476-5381.2012.02215.x. The pharmaceutical industry has been one of the main value-added industries in Europe and a major driver in world drug discovery. The pharmacological know-how and skill of British Pharmacology is a major national resource. Unfortunately, the pharmaceutical industry has had a very difficult time recently. The loss of revenue due to key compounds becoming generic, with insufficient replacement by new therapeutic agents, is incompatible with a continuing high research spend by industry. The UK has been particularly hard-hit in the last 2 years, which is a major problem for the sector (which generated £8 billion, with 78 000 high-value jobs in 2009), and even more so for the innumerable drug discovery and development scientists who have been made redundant. This project has been produced specifically for these scientists: people who have been made redundant and are looking for new employment, or have decided either to take time out, retire early, or simply want to return to their scientific roots, with the prospect of creating a unique knowledge base for pharmacology. You represent the most highly skilled, and specialized, workforce in the world, which is also necessary for many service industries and is highly embedded in academic research. This is a major national resource which must not be allowed to dissipate. At last, and we hope not too late, this is becoming a national priority. Furthermore, these difficulties arrive at a time when there are many more molecular targets identified, and there is a major requirement to define their physiological and potential pathological or therapeutic roles. One way in which you might consider lending your support is by contributing to the BPS's GRAC, and the NC-IUPHAR database (IUPHAR-DB). NC-IUPHAR has 60 subcommittees on specialized pharmacological areas where scientists freely give their time for articles on receptors or channels, and to populate IUPHAR-DB. Recently, the BPS and IUPHAR have collaborated to integrate GRAC and IUPHAR-DB on the Web, via a new resource: http://www.guidetopharmacology.org. The site features articles on all aspects of pharmacology, particularly new areas: microRNAs, epigenetics and transporters. One aspect that would be covered, alongside nomenclature and key pharmacology, would be also be the drug discovery challenges in each area. We would much appreciate if you have some time to help us populate http://www.guidetopharmacology.org and our databases with articles that would count as publication credits (NC-IUPHAR has an H-index of >60, with many citation classics) on areas where you have expertise. The key requirement is enthusiasm, access to the Web and mutual support. The outcome would be the further development of a major knowledge resource, maintenance and development of skills and of drug discovery platforms in the UK, and your work would be vital. For more information or to express an interest, please contact enquiries@guidetopharmacology.org.

Today's data-intensive, interdisciplinary research challenges scientists to keep up to date with key experimental techniques and tools reported in the literature. The International Union of Basic and Clinical Pharmacology Database (IUPHAR-DB) goes some way to addressing this need by providing expert-curated information sourced from primary literature and displayed in a user-friendly manner online. The database provides a channel for the IUPHAR Nomenclature Committee (NC-IUPHAR) to provide recommendations on the nomenclature of receptors and ion channels, to document their properties and the ligands that are useful for receptor characterization. Here we describe IUPHAR-DB's main features and provide examples of techniques for navigating and exploring the information. The database is freely available online at http://www.iuphar-db.org/.