Previous studies have indicated the antitumoral effect of human melanocytes, human melanoma cell lines expressing CB1 receptor (CB1), and of the peritumoral administration of endocannabinoids. In the present study, we systematically screened several human melanoma cell lines for the expression of CNR1 and demonstrated transcription of the authentic gene. The ...

The B7 homologues and their receptors regulate both peripheral tolerance and adaptive immunity. This field is rapidly evolving as new ligands and receptors are being identified. Much of the work supporting their role in the regulation of host anti-tumor immunity has been derived from experimental models and clinical trials in ...

Multiple functional implications have been suggested for a limited number of chemokines and their cognate receptors in melanoma pathogenesis. The purpose of this study was to investigate the potential role of the chemokine receptors CXCR4, CCR7, CCR9, and CCR10 as prognostic markers in human primary cutaneous melanoma. Chemokine receptor expression ...

Comment on: Opitz CA, et al. Nature 2011; 478:197-203.

Comment on: Opitz CA, et al. Nature 2011; 478:197-203.

The role of the glutamatergic system in cancer cell homeostasis has expanded exponentially over the last decade. Once thought to participate only in synaptic transmission and neuronal excitability, the presence of functional glutamate receptors have since been demonstrated in peripheral tissues. Most notable is the implication of glutamate receptors in ...

The effects of low concentrations of caffeine and ryanodine on field excitatory postsynaptic potentials (EPSPs) and long-term potentiation (LTP) were studied in CA1 region of slices of dorsal and ventral hippocampus (DH and VH, respectively). There was a striking difference between the two regions in the magnitude of effect of ...

BACKGROUND: /st>While producing good-quality analgesia, µ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of δ-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505). METHODS: /st>We measured receptor binding affinity in Chinese hamster ovary (CHO) ...

The present study examined effects of caffeine on antinociception by acetaminophen in the formalin test in mice. It demonstrates that caffeine 10mg/kg inhibits antinociception produced by acetaminophen 300mg/kg i.p. against phase 2 flinches. Chronic administration of caffeine in the drinking water (0.1, 0.3g/l) for 8days also inhibits the action of ...

Three new X-ray structures of a thermostabilized A(2A) adenosine receptor in complex with different antagonists reported by Doré et al. in this issue have advanced the understanding of molecular recognition for this receptor.

Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a ...

Abnormal blood lipids are the major modifiable risk factor underlying the development of cardiovascular disease. Niacin has a profound ability to reduce low-density lipoprotein-C, very low-density lipoprotein-C and triglycerides and is the most effective pharmacological agent to increase high-density lipoprotein-C. Recently, the receptor for niacin, GPR109A, was discovered. GPR109A in ...

A diet low in carbohydrates helps to reduce the amount of ingested calories and to maintain a healthy weight. With this in mind, food and beverage companies have reformulated a large number of their products, replacing sugar or high fructose corn syrup with several different types of zero-calorie sweeteners to ...

Caffeine robustly enhances transmitter release from the hippocampal mossy fiber terminals, although it remains uncertain whether calcium mobilization through presynaptic ryanodine receptors mediates this enhancement. In this study, we adopted a selective adenosine A1 blocker to assess relative contribution of A1 receptors and ryanodine receptors in caffeine-induced synaptic enhancement. Application ...

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A(2A) receptors (A(2A)Rs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in ...

We recently reported a series of 1-acyl-N-(biphenyl-4-ylmethyl)pyrrolidine-2-carboxamides as AT(1) receptor ligands. The most potent compound of the series, 1-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-pyrrolidine-2-carboxamide, showed an interesting affinity for the receptor. To investigate the influence of structure variations on affinity, the synthesis of additional compounds belonging to this series has been performed. Biological tests run ...

GPCR inhibitors are highly prevalent in modern therapeutics. However, interference with complex GPCR regulatory mechanisms leads to both therapeutic efficacy and adverse effects. Recently, the sphingosine-1-phosphate (S1P) receptor inhibitor FTY720 (also known as Fingolimod), which induces lymphopenia and prevents neuroinflammation, was adopted as a disease-modifying therapeutic in multiple sclerosis. Although ...

Abstract: We recently described (J. Med. Chem. 2008, 51, 6538-46) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to drug-like molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine tuning of the substituent ...

Systemic chemotherapy is the only current method of treatment that provides some chance for long-term survival in patients with advanced or metastatic cancer. γ-Tocotrienol is a natural form of vitamin E found in high concentrations in palm oil and displays potent anticancer effects, but limited absorption and transport of by ...

For most patients with chronic heartburn and regurgitation, step-down therapy to the lowest effective dose of proton pump inhibitors (PPIs) or treatment with a histamine-2 receptor antagonist (H2RA) is a reasonable, cost-effective approach.

Background  Secondary peristalsis is important for the clearance of retained food bolus or refluxate from the esophagus. The effects of the gamma aminobutyric acid receptor type B (GABA(B) ) agonist on secondary peristalsis remain unclear in humans. We aimed to investigate the effect of a GABA(B) agonist baclofen on esophageal ...

Chemokines and their receptors are central to the inflammatory process and are attractive therapeutic targets. Drugs that inhibit chemokine receptors are approved for the treatment of HIV infection and for stem cell mobilization, but none have been approved yet for the treatment of inflammatory and/or autoimmune diseases. We analyse the ...

The important role of the P2Y12 receptor in amplification of platelet activation and associated responses and the limitations associated with clopidogrel therapy have led to the development of novel inhibitors of this receptor. Three reversibly-binding P2Y12 inhibitors are in phase 3 development, ticagrelor, cangrelor and elinogrel. The pharmacology and clinical ...

The therapeutic class of HMG-CoA reductase inhibitors, the statins are central agents in the treatment of hypercholesterolaemia and the associated conditions of cardiovascular disease, obesity and metabolic syndrome. Although statin therapy is generally considered safe, a number of known adverse effects do occur, most commonly treatment-associated muscular pain. In vitro ...

INTRODUCTION AND HYPOTHESIS: Antimuscarinic agents appear to exert their therapeutic activity in overactive bladder (OAB) via blockade of the M(3) muscarinic receptor subtype. Antimuscarinics are broadly similar in efficacy, but their safety and tolerability profiles vary, which may reflect differences in muscarinic receptor selectivity profiles. METHODS: This review of available ...

To the Editor: Tocilizumab is a monoclonal antibody that competitively inhibits binding of interleukin-6 (IL-6) to its receptor. It is approved for treatment of rheumatoid arthritis (RA) as monotherapy or with methotrexate. We report a case of cytomegalovirus (CMV) disease complicating treatment with an IL-6 receptor antagonist.

Tramadol (Ultram, Ultracet) is a centrally acting synthetic opioid with analgesic efficacy comparable to codeine. Antinociception is attributed to low but effective affinity for the mu-opioid receptor (μ), as well as reuptake inhibition of the monoamines norepinephrine (NE) and serotonin (5HT). Dual action antidepressants mirtazapine (Remeron), duloxetine (Cymbalta), and most ...

Glutamatergic neurotransmission, particularly through the N-methyl-D-aspartate (NMDA) receptor, has drawn attention for its role in the pathophysiology of schizophrenia. This paper reviews the neurodevelopmental origin and genetic susceptibility of schizophrenia relevant to NMDA neurotransmission, and discusses the relationship between NMDA hypofunction and different domains of symptom in schizophrenia as well ...

Use of topical antihistamines in the treatment of allergic conjunctivitis has evolved over the past several decades as our knowledge of the nature of the underlying disease has progressed. Formulations for the eye typically employ H(1)-receptor antagonists with a dual action, both directly as competitors for histamine receptor occupancy and ...

The β-adrenergic blocker and 5-HT(1A) receptor antagonist pindolol has been combined with selective serotonin reuptake inhibitors (SSRIs) in patients with depressive and anxiety disorders to shorten the onset of the clinical action and/or increase the proportion of responders. The results of a previous study have shown that pindolol potentiates the ...

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current ...

Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that ...

Pain remains a major clinical challenge because there are no effective analgesics for some pain conditions and the mainstay analgesics for severe pain, opioids, have serious unwanted effects. There is a dire need for novel analgesics in the clinic. Imidazoline receptors are a family of three receptors (I(1), I(2) and ...

Serotonin type 3 (5-HT(3)) receptors are ligand-gated ion channels built by five subunits of diverse composition. In humans, five subunits exist (5-HT3A-E) which are encoded by the genes HTR3A-E and are expressed in various isoforms. Recently, the importance of factors influencing receptor expression became clear, such as chaperones and microRNAs. ...

Although there has been tremendous improvement in managing chronic kidney disease (CKD) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in the last 15 years, CKD still progresses. Therefore, new emerging strategies are needed. The gold standard still lies with optimum renin-angiotensin-aldosterone system blockade, although many questions remain ...

Despite abundant evidence from basic/preclinical research that excessive NMDAR (N-methyl-d-aspartate receptor) stimulation is a crucial step required for brain damage following a stroke, clinical trials for NMDAR blockers have all ended with disappointments. The past decade of stroke research has revealed distinct NMDAR subpopulations and many specific effectors downstream of ...

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease characterized by increasing pulmonary vascular resistance leading to right ventricular failure and premature death. Current therapies target three major pathways involving endothelin, prostacyclin and NO. Ambrisentan is an oral, once daily, selective endothelin receptor antagonist. AREAS COVERED: This review ...

Hereditary angioedema (HAE) is characterized by acute attacks of edema with multiple localizations, the laryngeal angioedema being the most potentially lethal. In HAE, C1-INH impairments cause episodic increase in kallikrein activity leading to attacks of angioedema. Several therapies have recently become available to treat or to prevent HAE attacks, and ...

Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel ...

Currently available antiplatelet agents have shown improved short- and long-term clinical outcomes but are associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of protease-activated receptor-1 for thrombin represents a potential novel strategy to reduce ischemic events without increasing the risk of ...

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA(A)R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABA(A)Rs located in the various parts of CNS are thought to be involved ...

BACKGROUND: Statin is a specific inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme involved in the cholesterol synthesis pathway. In addition to their long-known efficacy for lowering cholesterol, statins have also been reported to possess anabolic effects on bone. Simvastatin is reported to increase cancellous bone volume, bone ...

A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major ...

Incretin-based therapies, such as the injectable GLP-1 receptor agonists and orally administered DPP-4 inhibitors, have recently been introduced into clinical practice. At present, the GLP-1 receptor agonists need to be administered once or twice daily. Several once weekly GLP-1 receptor agonists are in phase 3 development. This review examines the ...

Cannabinoids are the active chemical components of Cannabis sativa (marijuana). The medical use of cannabis goes back over 5,000 years. Cannabinoids produce a very wide array of central and peripheral effects, some of which may have beneficial clinical applications. The discovery of cannabinoid receptors has spawned great interest within the ...

Much of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding ...

Binge drinking, frequently referred to clinically as problem or hazardous drinking, is a pattern of excessive alcohol intake characterized by blood alcohol levels ≥0.08 g% within a 2-h period. Here, we show that overexpression of α1 subunits of the GABA(A) receptor contributes to binge drinking, and further document that this involvement ...

Atherosclerosis and its clinical sequelae still represent the primary cause of death in Western societies. During the past 25 years, a novel drug class to treat dyslipidemia, a main risk factor for coronary artery disease, emerged: liver- and thyroid hormone receptor isoform β-selective analogs. The present review will discuss the ...

Over the past two decades the dopamine D2 receptor has been undoubtedly the most widely studied dopamine receptor for the therapeutic treatment of schizophrenia, as the majority of antipsychotics exhibit antagonism at this receptor. However, the cognitive symptoms of the disorder are mostly resistant to the majority of available antipsychotic ...

The melanocortin receptors are a subfamily of G-protein-coupled, rhodopsin-like receptors that are rapidly being acknowledged as an extremely promising target for pharmacological intervention in a variety of different inflammatory pathologies, including stroke. Stroke continues to be a leading cause of death worldwide, with risk factors including smoking, diabetes, hypertension and ...