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Special Issue "GPCR Based Drug Discovery"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 March 2013)

Special Issue Editor

Guest Editor
Dr. Sandra Siehler

Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry, WSJ-88.2.05, 4002 Basel, Switzerland
E-Mail
Interests: G protein-coupled receptors (GPCRs); G proteins; RhoGEF-Rho signaling; adenylyl cyclases; cellular signaling pathways; cell-based/ biochemical/ -physical assays for membrane proteins; cardiovascular pharmacology; drug discovery

Special Issue Information

Dear Colleagues,

Multiple G protein-coupled receptors (GPCRs) are present on the cell surface of every cell type, form complexes with other receptors and proteins, and transmit signals into the intracellular lumen to regulate key physiological events. Dysregulated GPCR signaling is causative for pathophysiological conditions, and targeting of GPCRs is hence widely utilized for therapeutic intervention. The recent advancements towards purification, in vitro reconstitution, and structural determination of GPCRs open up new avenues for biochemical –and physical strategies to complement classical cellular drug discovery approaches. Emerging cellular signaling aspects of GPCRs include new temporal and spatial insights, and emerging concepts on G12/13 and MAPK pathways, adenylyl cyclase isoform-specific signaling, and ligand pharmacology. Physiological cell systems containing native GPCRs and signaling environments become more important in early drug discovery to identify GPCR ligands with activities projectable to in vivo disease models and related pharmacodynamic readouts. The purpose of this special issue is to capture these novel facets of GPCR drug discovery.

Dr. Sandra Siehler
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • GPCR structures
  • biochemical/-physical approaches for GPCRs
  • kinetic analyses of GPCRs signaling
  • spatial signaling of GPCRs
  • cellular assays for GPCRs in recombinant versus primary cells/ differentiated stem cells
  • G12/13 signaling of GPCRs
  • GPCR-linked MAPK signaling pathways (ERK, p38MAPK, JNK)
  • adenylyl cyclases as mediators of GPCR signaling
  • pharmacology/ functional selectivity of GPCR ligands
  • pathophysiological signaling of GPCRs
  • in vivo pharmacodynamic assays for GPCRs

Published Papers (16 papers)

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Research

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Open AccessArticle The Three Catecholics Benserazide, Catechol and Pyrogallol are GPR35 Agonists
Pharmaceuticals 2013, 6(4), 500-509; doi:10.3390/ph6040500
Received: 6 March 2013 / Revised: 20 March 2013 / Accepted: 1 April 2013 / Published: 8 April 2013
Cited by 4 | PDF Full-text (939 KB) | HTML Full-text | XML Full-text
Abstract Nearly 1% of all clinically used drugs are catecholics, a family of catechol-containing compounds. Using label-free dynamic mass redistribution and Tango β-arrestin translocation assays, we show that several catecholics, including benserazide, catechol, 3-methoxycatechol, pyrogallol, (+)-taxifolin and fenoldopam, display agonistic activity against GPR35. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessArticle Dual-Color Bioluminescence Analysis for Quantitatively Monitoring G-Protein-Coupled Receptor and β-Arrestin Interactions
Pharmaceuticals 2011, 4(3), 457-469; doi:10.3390/ph4030457
Received: 13 December 2010 / Revised: 17 February 2011 / Accepted: 18 February 2011 / Published: 25 February 2011
Cited by 8 | PDF Full-text (1028 KB) | HTML Full-text | XML Full-text
Abstract
G protein-coupled receptors (GPCRs) are crucial elements in mammalian signal transduction, and are considered to represent potent drug targets. We have previously developed a GPCR assay system in cultured cells based on complementation of split fragments of click beetle (Pyrearinus termitilluminans)
[...] Read more.
G protein-coupled receptors (GPCRs) are crucial elements in mammalian signal transduction, and are considered to represent potent drug targets. We have previously developed a GPCR assay system in cultured cells based on complementation of split fragments of click beetle (Pyrearinus termitilluminans) luciferase. The interaction of GPCRs with its target, β-arrestin, resulted in strong emission of bioluminescence upon stimulation with its specific ligand. In this study, we improved precision of the GPCR assay system by using railroad worm (Phrixothrix hirtus) luciferase as an internal control. We generated stable cell lines harboring the railroad worm luciferase and quantitatively evaluate the extent of GPCR-β-arrestin interactions. We showed concentration-dependent bioluminescence responses for four GPCRs: β2-adrenoceptor, endothelin receptor type A, α2-adrenoceptor and human μ-opioid receptor. We also demonstrated that the variation of responses was reduced significantly by normalizing the data with bioluminescence from railroad worm luciferase. This assay system represents a simple and reliable approach for screening drug candidates in a high throughput manner. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)

Review

Jump to: Research, Other

Open AccessReview Targeting Platelet Thrombin Receptor Signaling to Prevent Thrombosis
Pharmaceuticals 2013, 6(8), 915-928; doi:10.3390/ph6080915
Received: 6 May 2013 / Revised: 18 July 2013 / Accepted: 26 July 2013 / Published: 2 August 2013
Cited by 3 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
Abstract
Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more
[...] Read more.
Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors
Pharmaceuticals 2012, 5(5), 417-446; doi:10.3390/ph5050417
Received: 3 February 2012 / Revised: 18 April 2012 / Accepted: 19 April 2012 / Published: 27 April 2012
Cited by 5 | PDF Full-text (533 KB) | HTML Full-text | XML Full-text
Abstract
G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating
[...] Read more.
G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs) linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers) or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs) in pathophysiology of diseases and as the potential candidate for drug discovery. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Functional and Structural Overview of G-Protein-Coupled Receptors Comprehensively Obtained from Genome Sequences
Pharmaceuticals 2011, 4(4), 652-664; doi:10.3390/ph4040652
Received: 17 February 2011 / Revised: 2 April 2011 / Accepted: 6 April 2011 / Published: 13 April 2011
Cited by 13 | PDF Full-text (948 KB) | HTML Full-text | XML Full-text
Abstract
An understanding of the functional mechanisms of G-protein-coupled receptors (GPCRs) is very important for GPCR-related drug design. We have developed an integrated GPCR database (SEVENS http://sevens.cbrc.jp/) that includes 64,090 reliable GPCR genes comprehensively identified from 56 eukaryote genome sequences, and overviewed the sequences
[...] Read more.
An understanding of the functional mechanisms of G-protein-coupled receptors (GPCRs) is very important for GPCR-related drug design. We have developed an integrated GPCR database (SEVENS http://sevens.cbrc.jp/) that includes 64,090 reliable GPCR genes comprehensively identified from 56 eukaryote genome sequences, and overviewed the sequences and structure spaces of the GPCRs. In vertebrates, the number of receptors for biological amines, peptides, etc. is conserved in most species, whereas the number of chemosensory receptors for odorant, pheromone, etc. significantly differs among species. The latter receptors tend to be single exon type or a few exon type and show a high ratio in the numbers of GPCRs, whereas some families, such as Class B and Class C receptors, have long lengths due to the presence of many exons. Statistical analyses of amino acid residues reveal that most of the conserved residues in Class A GPCRs are found in the cytoplasmic half regions of transmembrane (TM) helices, while residues characteristic to each subfamily found on the extracellular half regions. The 69 of Protein Data Bank (PDB) entries of complete or fragmentary structures could be mapped on the TM/loop regions of Class A GPCRs covering 14 subfamilies. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Molecular Approaches To Target GPCRs in Cancer Therapy
Pharmaceuticals 2011, 4(4), 567-589; doi:10.3390/ph4040567
Received: 11 March 2011 / Revised: 22 March 2011 / Accepted: 22 March 2011 / Published: 25 March 2011
Cited by 5 | PDF Full-text (454 KB) | HTML Full-text | XML Full-text
Abstract
Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells’ coexistence, cancer has to deceive cell-cell communication in order
[...] Read more.
Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells’ coexistence, cancer has to deceive cell-cell communication in order to grow and spread. GPCRs play a critical role in this process. Despite the fact that GPCRs represent one of the most common drug targets, current medical practice includes only a few anticancer compounds directly acting on their signaling. Many approaches can be envisaged to target GPCRs involved in oncology. Beyond interfering with GPCRs signaling by using agonists or antagonists to prevent cell proliferation, favor apoptosis, induce maturation, prevent migration, etc., the high specificity of the interaction between the receptors and their ligands can be exploited to deliver toxins, antineoplastic drugs or isotopes to transformed cells. In this review we describe the strategies that are in use, or appear promising, to act directly on GPCRs in the fight against neoplastic transformation and tumor progression. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators
Pharmaceuticals 2011, 4(3), 509-523; doi:10.3390/ph4030509
Received: 3 February 2011 / Revised: 9 March 2011 / Accepted: 9 March 2011 / Published: 14 March 2011
Cited by 10 | PDF Full-text (690 KB) | HTML Full-text | XML Full-text
Abstract
G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in
[...] Read more.
G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor’s innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Figures

Open AccessReview Soft X-ray Laser Microscopy of Lipid Rafts towards GPCR-Based Drug Discovery Using Time-Resolved FRET Spectroscopy
Pharmaceuticals 2011, 4(3), 524-550; doi:10.3390/ph4030524
Received: 17 December 2010 / Revised: 7 March 2011 / Accepted: 7 March 2011 / Published: 14 March 2011
PDF Full-text (707 KB) | HTML Full-text | XML Full-text
Abstract
Many signaling molecules involved in G protein-mediated signal transduction, which are present in the lipid rafts and believed to be controlled spatially and temporally, influence the potency and efficacy of neurotransmitter receptors and transporters. This has focus interest on lipid rafts and the
[...] Read more.
Many signaling molecules involved in G protein-mediated signal transduction, which are present in the lipid rafts and believed to be controlled spatially and temporally, influence the potency and efficacy of neurotransmitter receptors and transporters. This has focus interest on lipid rafts and the notion that these microdomains acts as a kind of signaling platform and thus have an important role in the expression of membrane receptor-mediated signal transduction, cancer, immune responses, neurotransmission, viral infections and various other phenomena due to specific and efficient signaling according to extracellular stimuli. However, the real structure of lipid rafts has not been observed so far due to its small size and a lack of sufficiently sophisticated observation systems. A soft X-ray microscope using a coherent soft X-ray laser in the water window region (2.3–4.4 nm) should prove to be a most powerful tool to observe the dynamic structure of lipid rafts of several tens of nanometers in size in living cells. We have developed for the X-ray microscope a new compact soft X-ray laser using strongly induced plasma high harmonic resonance. We have also developed a time-resolved highly sensitive fluorescence resonance energy transfer (FRET) system and confirmed protein-protein interactions coupled with ligands. The simultaneous use of these new tools for observation of localization of G-protein coupled receptors (GPCRs) in rafts has become an important and optimum tool system to analyze the dynamics of signal transduction through rafts as signaling platform. New technology to visualize rafts is expected to lead to the understanding of those dynamics and innovative development of drug discovery that targets GPCRs localized in lipid rafts. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview GPCRs Revisited: New Insights Lead to Novel Drugs
Pharmaceuticals 2011, 4(2), 244-272; doi:10.3390/ph4020244
Received: 6 December 2010 / Revised: 22 December 2010 / Accepted: 18 January 2011 / Published: 25 January 2011
Cited by 12 | PDF Full-text (216 KB) | HTML Full-text | XML Full-text
Abstract
GPCRs play a critical role in human physiology and are a prime target for drug discovery globally. Novel insights into the functions of GPCRs are providing unique approaches to modulate these proteins to generate unique drug candidates. Next generation ligands include those with
[...] Read more.
GPCRs play a critical role in human physiology and are a prime target for drug discovery globally. Novel insights into the functions of GPCRs are providing unique approaches to modulate these proteins to generate unique drug candidates. Next generation ligands include those with novel pharmacologies such as allosteric regulators as well pepducins, that affect the interaction of GPCRs with G proteins, to either block selective receptor signaling pathways or mimic the actions of intracellular domains of receptors, thereby activating GPCRs to signal selectively to intracellular pathways. We will review these new concepts and then discuss how they may be exploited using modern discovery technologies to provide novel drug candidates for the future. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Expanding the Concept of G Protein-Coupled Receptor (GPCR) Dimer Asymmetry towards GPCR-Interacting Proteins
Pharmaceuticals 2011, 4(2), 273-284; doi:10.3390/ph4020273
Received: 6 December 2010 / Revised: 7 January 2011 / Accepted: 14 January 2011 / Published: 25 January 2011
Cited by 3 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
G protein-coupled receptors (GPCRs), major targets of drug discovery, are organized in dimeric and/or oligomeric clusters. The minimal oligomeric unit, the dimer, is composed of two protomers, which can behave differently within the dimer. Several examples of GPCR asymmetry within dimers at the
[...] Read more.
G protein-coupled receptors (GPCRs), major targets of drug discovery, are organized in dimeric and/or oligomeric clusters. The minimal oligomeric unit, the dimer, is composed of two protomers, which can behave differently within the dimer. Several examples of GPCR asymmetry within dimers at the level of ligand binding, ligand-promoted conformational changes, conformational changes within transmembrane domains, G protein coupling, and most recently GPCR-interacting proteins (GIPs), have been reported in the literature. Asymmetric organization of GPCR dimers has important implications on GPCR function and drug design. Indeed, the extension of the “asymmetry concept” to GIPs adds a new level of specific therapeutic intervention. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Original Fluorescent Ligand-Based Assays Open New Perspectives in G-Protein Coupled Receptor Drug Screening
Pharmaceuticals 2011, 4(1), 202-214; doi:10.3390/ph4010202
Received: 1 December 2010 / Revised: 23 December 2010 / Accepted: 24 December 2010 / Published: 18 January 2011
Cited by 12 | PDF Full-text (265 KB) | HTML Full-text | XML Full-text
Abstract
The identification of new drugs exhibiting reduced adverse side-effects constitutes a great challenge for the next decade. Various steps are needed to screen for good ligand candidates and one of them is the evaluation of their binding properties. New strategies based on fluorescence
[...] Read more.
The identification of new drugs exhibiting reduced adverse side-effects constitutes a great challenge for the next decade. Various steps are needed to screen for good ligand candidates and one of them is the evaluation of their binding properties. New strategies based on fluorescence measurement constitute excellent alternatives to the traditional radioactive assays. Less hazardous, faster and cheaper, these methods also exhibit very good sensitivity and can be used on various biological models such as heterologous expression systems or native tissues. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis
Pharmaceuticals 2011, 4(1), 117-137; doi:10.3390/ph4010117
Received: 30 November 2010 / Revised: 25 December 2010 / Accepted: 4 January 2011 / Published: 4 January 2011
Cited by 5 | PDF Full-text (251 KB) | HTML Full-text | XML Full-text
Abstract
Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and
[...] Read more.
Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P1-S1P5). Among them, S1P1, S1P2 and S1P3 are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of Gi signaling pathway via S1P3 and probably S1P1, although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors except S1P2 and act as an immunosuppressant by downregulating S1P1 on lymphocytes, inhibits atherosclerosis in LDL receptor-null mice and apoE-null mice through the inhibition of lymphocyte and macrophage functions and probably stimulation of EC functions, without influencing plasma lipid concentrations. In contrast to S1P1 and S1P3, S1P2 facilitates atherosclerosis by activating G12/13-Rho-Rho kinase (ROCK) in apoE-null mice. S1P2 mediates transmigration of monocytes into the arterial intima, oxidized LDL accumulation and cytokine secretion in monocyte-derived macrophages, and eNOS inhibition and cytokine secretion in ECs through Rac inhibition, NF-kB activation and 3’-specific phosphoinositide phosphatase (PTEN) stimulation downstream of G12/13-Rho-ROCK. Systemic long-term administration of a selective S1P2-blocker remarkably inhibits atherosclerosis without overt toxicity. Thus, multiple S1P receptors positively and negatively regulate atherosclerosis through multitudes of mechanisms. Considering the essential and multi-faceted role of S1P2 in atherogenesis and the impact of S1P2 inactivation on atherosclerosis, S1P2 is a particularly promising therapeutic target for atherosclerosis. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview GPCR Conformations: Implications for Rational Drug Design
Pharmaceuticals 2011, 4(1), 7-43; doi:10.3390/ph4010007
Received: 24 November 2010 / Revised: 20 December 2010 / Accepted: 21 December 2010 / Published: 23 December 2010
Cited by 9 | PDF Full-text (1717 KB) | HTML Full-text | XML Full-text
Abstract
G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members of
[...] Read more.
G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members of this family. Tremendous contributions to our understanding of GPCR structure and dynamics have come from both indirect and direct structural characterization techniques. Key features of GPCR conformations derived from both types of characterization techniques are reviewed. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Jak2 Tyrosine Kinase: A Potential Therapeutic Target for AT1 Receptor Mediated Cardiovascular Disease
Pharmaceuticals 2010, 3(11), 3478-3493; doi:10.3390/ph3113478
Received: 21 September 2010 / Revised: 27 October 2010 / Accepted: 8 November 2010 / Published: 9 November 2010
Cited by 2 | PDF Full-text (307 KB) | HTML Full-text | XML Full-text
Abstract
Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT1-R) blockade, and aldosterone receptor antagonism. The
[...] Read more.
Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT1-R) blockade, and aldosterone receptor antagonism. The Jak2 signaling pathway is intricately coupled to the AT1-R signaling processes involved in hypertension. Here, we review the involvement of Jak2 in the pathogenesis of hypertension, and its potential as a therapeutic target for treatment of AT1-R mediated cardiovascular disease. Jak2 may provide a rational therapeutic approach for patients whose blood pressure is not controlled by standard therapies. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Role of the G Protein-Coupled Receptor, mGlu1, in Melanoma Development
Pharmaceuticals 2010, 3(9), 2821-2837; doi:10.3390/ph3092821
Received: 2 July 2010 / Revised: 18 August 2010 / Accepted: 20 August 2010 / Published: 26 August 2010
PDF Full-text (213 KB) | HTML Full-text | XML Full-text
Abstract
Melanoma remains one of the cancers for which a decline in morbidity has not been achieved with current scientific and medical advances. Mono-therapies targeting melanoma have been largely ineffective, increasing the need for identification of new drugable targets. Multiple tumor suppressors and oncogenes
[...] Read more.
Melanoma remains one of the cancers for which a decline in morbidity has not been achieved with current scientific and medical advances. Mono-therapies targeting melanoma have been largely ineffective, increasing the need for identification of new drugable targets. Multiple tumor suppressors and oncogenes that impart genetic predisposition to melanoma have been identified and are being studied in an attempt to provide insight on the development of anti-melanoma therapies. Metabotropic Glutamate Receptor I (GRM1) has recently been implicated as a novel oncogene involved in melanomagenesis. GRM1 (mGlu1, protein) belongs to the G protein coupled receptor (GPCR) super family and is normally functional in the central nervous system. Our group showed in a transgenic mouse model system that ectopic expression of Grm1 in melanocytes is sufficient to induce spontaneous melanoma development in vivo. GPCRs are some of the most important therapeutic drug targets discovered to date and they make up a significant proportion of existing therapies. This super family of transmembrane receptors has wide spread expression and interacts with a diverse array of ligands. Diverse physiological responses can be induced by stimulator(s) or suppressor(s) of GPCRs, which contributes to their attractiveness in existing and emerging therapies. GPCR targeting therapies are employed against a variety of human disorders including those of the central nervous system, cardiovascular, metabolic, urogenital and respiratory systems. In the current review, we will discuss how the identification of the oncogenic properties of GRM1 opens up new strategies for the design of potential novel therapies for the treatment of melanoma. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)

Other

Jump to: Research, Review

Open AccessOpinion Neuropeptide Receptors: Novel Targets for HIV/AIDS Therapeutics
Pharmaceuticals 2011, 4(3), 485-493; doi:10.3390/ph4030485
Received: 3 February 2011 / Revised: 4 March 2011 / Accepted: 7 March 2011 / Published: 9 March 2011
Cited by 2 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC) receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate
[...] Read more.
The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC) receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate the infection of HIV by a signal transduction pathway that appears to regulate viral integration. In this article, the affects of VPAC stimulation on HIV infection will be reviewed and approaches for the development of HIV/AIDS therapeutics that target these receptors will be described. Novel HIV/AIDS therapeutics are urgently required to stem the continued spread of this disease, particularly in underdeveloped countries. Drug design to inhibit signaling through VPAC1 and stimulate signaling through VPAC2 could lead to alternative therapies for the treatment and/or prevention of HIV/AIDS. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)

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