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Sample records for receptor agonist treatment

  1. Melatonin receptor agonists: new options for insomnia and depression treatment.

    PubMed

    Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco

    2011-12-01

    The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years. © 2010 Blackwell Publishing Ltd.

  2. Peripheral biomarkers of cognitive response to dopamine receptor agonist treatment.

    PubMed

    Ersche, Karen D; Roiser, Jonathan P; Lucas, Mark; Domenici, Enrico; Robbins, Trevor W; Bullmore, Edward T

    2011-04-01

    Using biological markers to objectively measure addiction severity or to identify individuals who might benefit most from pro-cognitive treatment could potentially revolutionize neuropsychopharmacology. We investigated the use of dopamine receptor mRNA levels in circulating blood cells as predictors of cognitive response following dopamine agonist treatment, and as biomarkers of the severity of stimulant drug dependence. We employed a double-blind, placebo-controlled cross-over design, administering a single dose of the selective dopamine D(2/3) receptor agonist pramipexole (0.5 mg) to increase dopamine transmission in one session and a placebo treatment in another session in 36 volunteers. Half the volunteers had a formal diagnosis of stimulant dependence, while half had no psychiatric history. Participants performed neurocognitive tests from the CANTAB battery on both occasions, and stimulant-dependent individuals rated drug craving using visual analog scales. Whole-blood mRNA levels were measured for three dopamine-related genes: DRD3 and DRD4 (dopamine receptors), and catechol-O-methyltransferase (COMT; a dopamine catabolic enzyme). Stimulant users performed worse than healthy volunteers on the cognitive tests. The variation in peripheral dopamine D(3) receptor mRNA expression explained over one quarter of the variation in response to pramipexole on the spatial working memory test across all participants. The severity of stimulant dependence was also significantly associated with peripheral COMT mRNA expression in stimulant users. Peripheral expression of dopamine-related genes may be useful as a biomarker of cognitive response to dopamine agonist drugs and of severity of addiction to dopamine-releasing stimulant drugs.

  3. [Treatment of GLP1 receptor agonists and body mass control].

    PubMed

    Žák, Petr; Olšovský, Jindřich

    2015-04-01

    The prevalence of obesity continues to be increasing in all age groups in most countries of the European Union (EU). Many obese people have a history of several successful weight losses, but very few are able to maintain the weight loss over a longer period of time. Initiation of the GLP1 RA administration during weight loss maintenance would inhibit weight loss-induced increases in soluble leptin receptor plasma concentrations resulting in higher level of free leptin thereby preventing weight regain. In contrast initiation of insulin treatment in type 2 diabetes patients is frequently accompanied with weight gain. The GLP1 administration results in HbA1c decrease accompanied with weight loss, presents attractive alternative to basal insulin. The question remains to be answered in the future, if the GLP1 RA administration is generally more frequently started in antiobese than antidiabetes implication.

  4. [Melatonin receptor agonist].

    PubMed

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.

  5. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

    PubMed Central

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T.; Abbruscato, Thomas J.

    2015-01-01

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10 nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10 nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype. PMID:25801116

  6. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment.

    PubMed

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T; Abbruscato, Thomas J

    2015-06-03

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

  7. [Cardiovascular effects of GLP-1 receptor agonist treatment: focus on liraglutide].

    PubMed

    Haluzík, Martin; Trachta, Pavel; Mráz, Miloš

    2015-01-01

    Cardiovascular risk reduction is the major aim of type 2 diabetes mellitus treatment. The effects of various antidiabetics on the cardiovascular complications are currently under careful scrutiny. Incretin-based therapy that utilizes the effects of glucagon-like peptide 1 (GLP-1) or stimulation of its receptor by GLP-1 receptor agonists represents one of the most promising approaches from the potential cardiovascular risk reduction point of view. Experimental studies have shown that the GLP-1 and GLP-1 agonists treatment improves endothelial function, decrease blood pressure and protects myocardium during experimentally-induced ischemia. Clinical studies with GLP-1 receptor agonists consistently show that, in addition to good antidiabetic efficacy, its long-term administration decreases blood pressure, body weight and improves circulating lipid levels while slightly increasing heart rate. In this paper, we focus on the cardiovascular effects of GLP-1 receptor agonist liraglutide. Preliminary analyses of cardiovascular complications in phase III trials with liraglutide indicate its good cardiovascular safety. A possibility of cardioprotective effects of liraglutide remains still open and is currently studied within a prospective cardiovascular trial LEADER.

  8. Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke

    PubMed Central

    2014-01-01

    Background Lipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPARα agonists. Results In order to identify potential therapeutic targets positively modulated by pre-treatment with the PPARα agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPARα agonists treatment while it was strongly increased in ischemia-reperfusion. Conclusions Pre-treatment with PPARα agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPARα agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis

  9. The safety and tolerability of GLP-1 receptor agonists in the treatment of type-2 diabetes.

    PubMed

    Russell-Jones, D

    2010-09-01

    Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

  10. Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder

    PubMed Central

    Belkin, Molly R; Schwartz, Thomas L

    2015-01-01

    Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD) is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA)-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and symptoms of hyperarousal often persist. This article specifically reviews the literature on alpha-2 receptor agonist use for the treatment of PTSD and concludes that while the evidence base is limited, these agents might be considered useful when SSRIs fail to treat symptoms of agitation and hyperarousal in patients with PTSD. PMID:26322115

  11. Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder.

    PubMed

    Belkin, Molly R; Schwartz, Thomas L

    2015-01-01

    Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD) is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA)-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and symptoms of hyperarousal often persist. This article specifically reviews the literature on alpha-2 receptor agonist use for the treatment of PTSD and concludes that while the evidence base is limited, these agents might be considered useful when SSRIs fail to treat symptoms of agitation and hyperarousal in patients with PTSD.

  12. GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings.

    PubMed

    Cousins, Michael S; Roberts, David C S; de Wit, Harriet

    2002-02-01

    A growing preclinical and clinical literature suggests that GABA(B) receptor agonists promote abstinence and reduce the use of cocaine, heroin, alcohol and nicotine. The purpose of this paper is to critically review these data. GABA(B) receptor agonists, such as baclofen, appear to reduce the reinforcing effects of abused drugs in animal models under multiple experimental procedures. This occurs at doses that have little effect on responding for other positive reinforcers such as food or water. We review evidence that these potential therapeutic effects may be mediated by modulation of mesolimbic dopamine neurons. This review also examines the preliminary clinical data from studies of the efficacy of baclofen for treatment of cocaine, alcohol, and nicotine dependence. We suggest that these preliminary data provide a rationale for conducting more systematic studies of the effects of GABA(B) receptor agonists as treatment for drug abuse. This line of research may also improve our understanding of the neurochemical mechanisms underlying the drug dependence process.

  13. Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan.

    PubMed

    Suzuki, Go; Sato, Kentaro; Isobe, Tomohiko; Takigami, Hidetaka; Brouwer, Abraham; Nakayama, Kei

    2015-09-15

    Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate > clobetasone butyrate > betamethasone 17-valerate > difluprednate > betamethasone 17,21-dipropionate > Dex > betamethasone > 6α-methylprednisolone > prednisolone > cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from < 3.0-78 ng L(-1) (median: 29 ng L(-1), n = 50). To evaluate the contribution of the target GCs, theoretical Dex-EQs were calculated by multiplying the concentrations of each GC by its respective REP. Our calculation of Dex-EQ contribution for individual GR agonists indicated that the well-known GCs cortisol and Dex should not be given priority for subsequent in vivo testing, monitoring and removal experiments, but rather the highly potent synthetic GCs clobetasol propionate and betamethasone 17-valerate (REP = 28 and 3.1) as well as other unidentified compounds are important GR agonists in STP effluents in Japan.

  14. Investigational melatonin receptor agonists.

    PubMed

    Hardeland, Rüdiger

    2010-06-01

    Melatonin is a major chronobiological regulator involved in circadian phasing, sleep, and numerous other functions including cyto-/neuroprotection, immune modulation, and energy metabolism. The suitability of melatonin as a drug is limited because of its short half-life. Therefore, various indolic and non-indolic melatonergic agonists have been developed. Frequent health problems such as sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance are targeted by melatonergic agonists. Various synthetic melatonergic drugs are compared with regard to receptor affinities, selectivity, effects on sleep, endogenous melatonin, circadian phase and insulin-related metabolism. The chemical design of melatonin receptor agonists is discussed in relation to consequences for receptor affinity, selectivity, metabolism, and spectrum of effects. Melatonergic agonists are suitable for phase-shifting circadian rhythms, and may be used for treating disorders related to circadian dysfunction including sleep difficulties. Facilitation of sleep onset is a general property, whereas promotion of sleep maintenance is demonstrable but not always fully sufficient. Details are especially available for tasimelteon. Support of insulin sensitivity may become a new area of application for compounds such as NEU-P11. Some drugs acting additionally as serotonergic antagonists display antidepressant properties.

  15. Treatment of young-onset Parkinson's disease: role of dopamine receptor agonists.

    PubMed

    Kostić, Vladimir S

    2009-12-01

    For mostly arbitrary reasons, the term "juvenile parkinsonism" is restricted to patients aged 20 years or younger, and "young-onset PD" (YOPD) is onset between ages 21 and 40 years. Previous studies suggest that YOPD has a slower disease progression and a greater incidence and earlier appearance of L-dopa-induced dyskinesias and motor fluctuations. Therefore, our therapeutic strategies have to respect the fact that YOPD patients face many years of gradual progression of disease and disability, a greater probability for developing various adverse effects of treatment, and worsening of quality of life. As an individually tailored treatment should be our primary goal, we must bear in mind that the needs and expectations of YOPD patients are different from those of their older counterparts. The therapeutic strategy for YOPD patients should include a relatively low threshold for initiation of treatment, and initiating treatment with a dopamine receptor agonist while maintaining an individually adjusted, moderately high threshold for switching to or adding L-dopa in cases where treatment response is suboptimal or if problematic adverse effects develop. It has been shown that some dopamine receptor agonists may also have antidepressive efficacy, thus potentially managing an additional problem associated with PD. Copyright 2009 Elsevier Ltd. All rights reserved.

  16. Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus.

    PubMed

    Yoshimoto, Ryo; Miyamoto, Yasuhisa; Shimamura, Ken; Ishihara, Akane; Takahashi, Kazuhiko; Kotani, Hidehito; Chen, Airu S; Chen, Howard Y; Macneil, Douglas J; Kanatani, Akio; Tokita, Shigeru

    2006-09-12

    Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

  17. Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists

    PubMed Central

    Watterson, Kenneth R.; Hudson, Brian D.; Ulven, Trond; Milligan, Graeme

    2014-01-01

    Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programs within industry and academia aimed at improving the safety and effectiveness of these potential treatments. PMID:25221541

  18. [Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes].

    PubMed

    Salvador, Javier; Andrada, Patricia

    2014-01-01

    The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

  19. Novel Retinoic Acid Receptor Alpha Agonists for Treatment of Kidney Disease

    PubMed Central

    Liu, Ruijie; Li, Zhengzhe; Chen, Yibang; Evans, Todd; Chuang, Peter; Das, Bhaskar; He, John Cijiang

    2011-01-01

    Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN. PMID:22125642

  20. Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist.

    PubMed

    Esposito, Angela; Criscitiello, Carmen; Gelao, Lucia; Pravettoni, Gabriella; Locatelli, Marzia; Minchella, Ida; Di Leo, Maria; Liuzzi, Rita; Milani, Alessandra; Massaro, Mariangela; Curigliano, Giuseppe

    2015-11-01

    Cancer cachexia is a multi-organ, multifactorial and often irreversible syndrome affecting many patients with cancer. Cancer cachexia is invariably associated with weight loss, mainly from loss of skeletal muscle and body fat, conditioning a reduced quality of life due to asthenia, anorexia, anaemia and fatigue. Treatment options for treating cancer cachexia are limited. The approach is multimodal and may include: treatment of secondary gastrointestinal symptoms, nutritional treatments, drug, and non-drug treatments. Nutritional counselling and physical training may be beneficial in delaying or preventing the development of anorexia-cachexia. However, these interventions are limited in their effect, and no definitive pharmacological treatment is available to address the relevant components of the syndrome. Anamorelin is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. It represents a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. In this review we examine the mechanisms of anamorelin by which it contrasts catabolic states, its role in regulation of metabolism and energy homeostasis, the data of recent trials in the setting of cancer cachexia and its safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review.

    PubMed

    Østergaard, L; Frandsen, Christian S; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.

  2. Inhaled P2Y2 receptor agonists as a treatment for patients with Cystic Fibrosis lung disease.

    PubMed

    Kellerman, Don; Evans, Richard; Mathews, Dave; Shaffer, Christy

    2002-12-05

    P2Y(2) receptor agonists are a new class of compounds that are being evaluated as a treatment for the pulmonary manifestations of Cystic Fibrosis (CF). Results of preclinical research suggest that these compounds inhibit sodium absorption, restore chloride conductance and rehydrate the CF airway surface. In addition, P2Y(2) receptor agonists have been shown to enhance ciliary beat frequency and increase mucociliary clearance in animals and subjects with impaired mucociliary clearance. The normalization of airway surface liquid and enhancement of lung clearance is expected to provide a clinical benefit to CF patients. A number of P2Y(2) agonist compounds have been evaluated in healthy subjects and patients with CF. Most recently, INS37217, a metabolically stable and potent P2Y(2) agonist has been developed and studies have shown it to be well-tolerated when given via inhalation. This compound is currently being evaluated in children and adults with CF lung disease.

  3. [Treatment strategy for elderly diabetic patient with insulin or GLP-1 receptor agonist].

    PubMed

    Ando, Yasuyo

    2013-11-01

    It has been established that diabetes is an independent risk factor for microvascular and macrovascular complications, and many studies indicate that diabetic subjects are at greater risk of dementia, depression and fracture. Risk reductions for microvascular, macrovascular and death were observed by intensive therapy using insulin or oral diabetic agents. But a history of hypoglycemia was increased myocardial infarction, mortality, dementia and fracture. So it is important that optimum glycemic control has to be achieved without hypoglycemia. Treatment with a long-acting basal insulin analogue or glucagon-like peptide-1(GLP-1) receptor agonist, provide effective glycemic control without serious hypoglycemia in elderly patients. Self-monitoring of blood glucose might be effective in improving glycemic control in elderly patients, and it is useful for the diagnosis of hypoglycemia.

  4. Effects of repeated treatment with the dopamine D2/D3 receptor partial agonist aripiprazole on striatal D2/D3 receptor availability in monkeys

    PubMed Central

    Czoty, Paul W.; Gage, H. Donald; Garg, Pradeep K.; Garg, Sudha; Nader, Michael A.

    2013-01-01

    Rationale Chronic treatment with dopamine (DA) receptor agonists and antagonists can differentially affect measures of DA D2/D3 receptor number and function, but the effects of chronic treatment with a partial D2/D3 receptor agonist are not clear. Objective We used a within-subjects design in male cynomolgus monkeys to determine the effects of repeated (17-day) treatment with the D2/D3 receptor partial agonist aripiprazole (ARI; 0.03 mg/kg and 0.1 mg/kg i.m.) on food-reinforced behavior (n=5) and on D2/D3 receptor availability as measured with positron emission tomography (PET; n=9). Methods Five monkeys responded under a fixed-ratio 50 schedule of food reinforcement and D2/D3 receptor availability was measured before and four days after ARI treatment using PET and the D2/D3 receptor-selective radioligand [18F]fluoroclebopride (FCP). Four additional monkeys were studied using [11C]raclopride and treated sequentially with each dose of ARI for 17 days. Results ARI decreased food-maintained responding with minimal evidence of tolerance. Repeated ARI administration increased FCP and raclopride distribution volume ratios (DVRs) in the caudate nucleus and putamen in most monkeys, but decreases were observed in monkeys with the highest baseline DVRs. Conclusions The results indicate that repeated treatment with a low efficacy DA receptor partial agonist produces effects on brain D2/D3 receptor availability that are qualitatively different from those of both high-efficacy receptor agonists and antagonists, and suggest that the observed individual differences in response to ARI treatment may reflect its partial agonist activity. PMID:24077804

  5. Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability.

    PubMed

    Fairfax, Benjamin P; Pitcher, Julie A; Scott, Mark G H; Calver, Andrew R; Pangalos, Menelas N; Moss, Stephen J; Couve, Andrés

    2004-03-26

    GABA(B) receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. The dynamic control of the cell surface stability of GABA(B) receptors is likely to be of fundamental importance in the modulation of receptor signaling. Presently, however, this process is poorly understood. Here we demonstrate that GABA(B) receptors are remarkably stable at the plasma membrane showing little basal endocytosis in cultured cortical and hippocampal neurons. In addition, we show that exposure to baclofen, a well characterized GABA(B) receptor agonist, fails to enhance GABA(B) receptor endocytosis. Lack of receptor internalization in neurons correlates with an absence of agonist-induced phosphorylation and lack of arrestin recruitment in heterologous systems. We also demonstrate that chronic exposure to baclofen selectively promotes endocytosis-independent GABA(B) receptor degradation. The effect of baclofen can be attenuated by activation of cAMP-dependent protein kinase or co-stimulation of beta-adrenergic receptors. Furthermore, we show that increased degradation rates are correlated with reduced receptor phosphorylation at serine 892 in GABA(B)R2. Our results support a model in which GABA(B)R2 phosphorylation specifically stabilizes surface GABA(B) receptors in neurons. We propose that signaling pathways that regulate cAMP levels in neurons may have profound effects on the tonic synaptic inhibition by modulating the availability of GABA(B) receptors.

  6. NEURONAL NICOTINIC RECEPTOR AGONISTS FOR THE TREATMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: FOCUS ON COGNITION

    PubMed Central

    Wilens, Timothy E.; Decker, Michael W.

    2010-01-01

    Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach. PMID:17689498

  7. Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases.

    PubMed

    Nettekoven, Matthias; Adam, Jean-Michel; Bendels, Stefanie; Bissantz, Catarina; Fingerle, Jürgen; Grether, Uwe; Grüner, Sabine; Guba, Wolfgang; Kimbara, Atsushi; Ottaviani, Giorgio; Püllmann, Bernd; Rogers-Evans, Mark; Röver, Stephan; Rothenhäusler, Benno; Schmitt, Sebastien; Schuler, Franz; Schulz-Gasch, Tanja; Ullmer, Christoph

    2016-01-19

    The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small-molecule CB2 receptor agonists were identified from a high-throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure-activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3S)-1-[5-tert-butyl-3-[(1-cyclopropyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol (39), was tested in a kidney ischemia-reperfusion model, in which it showed efficacy at a dose of 10 mg kg(-1) (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg(-1) per day significantly decreased the amount of fibrosis by ∼ 40% which was induced by unilateral ureter obstruction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

    PubMed

    Moon, Ho-Sang; Kim, Mi-Kyung; Son, Moon-Ho

    2011-07-01

    Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

  9. Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists.

    PubMed

    Farzin, Davood; Asghari, Ladan; Nowrouzi, Mahvash

    2002-06-01

    The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.

  10. Overview of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Patients with Type 2 Diabetes.

    PubMed

    Tran, Kelvin Lingjet; Park, Young In; Pandya, Shalin; Muliyil, Navin John; Jensen, Brandon David; Huynh, Kovin; Nguyen, Quang T

    2017-06-01

    It is estimated that 29.1 million people or 9.3% of the US population have diabetes, which contributes to considerable medical and financial burden. Type 2 diabetes mellitus is characterized by insulin resistance and insulin secretion impairment leading to hyperglycemia. The presence of insulin resistance is strongly correlated with obesity. This article reviews the available glucagon-like peptide-1 (GLP-1) receptor agonists and their role in the management of patients with diabetes, to help guide the selection of the most suitable agent for the individualized treatment of patients with type 2 diabetes. This article reviews the evidence from phase 3 clinical trials for each of the 5 GLP-1 receptor agonists by comparing them against one another and with other existing therapies, including metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas. Incretin-based therapies have emerged as attractive agents for the treatment of type 2 diabetes. They target the GLP-1 hormone, which is partly responsible for insulin release and for attenuating hyperglycemia during meals (ie, the incretin effect). The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4 inhibitors, which prevent the breakdown of GLP-1. Both classes are attractive options, given their glucose-lowering effects without the adverse effects of hypoglycemia and weight gain. The different mechanisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit at the expense of slightly increased gastrointestinal symptoms. These agents exert their effects by improving glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output, and decreasing the rate of gastric emptying, thereby reducing appetite. Currently, 5 GLP-1 receptor agonists are available, including exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide; semaglutide may soon become available as the newest

  11. Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.

    PubMed

    Marcus, Monica M; Björkholm, Carl; Malmerfelt, Anna; Möller, Annie; Påhlsson, Ninni; Konradsson-Geuken, Åsa; Feltmann, Kristin; Jardemark, Kent; Schilström, Björn; Svensson, Torgny H

    2016-09-01

    Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

  12. Treatment with oestrogen-receptor agonists or oxytocin in conjunction with exercise protects against myocardial infarction in ovariectomized rats.

    PubMed

    Bulut, Erman Caner; Abueid, Leyla; Ercan, Feriha; Süleymanoğlu, Selami; Ağırbaşlı, Mehmet; Yeğen, Berrak Ç

    2016-05-01

    What is the central question of this study? Could the activation of oxytocin or oestrogen receptors be protective against myocardial injury after ovariectomy? If so, would exercising have an additional ameliorating effect? What is the main finding and its importance? The results revealed that when accompanied by exercise, both oestrogen receptor agonists and oxytocin improved cardiac dysfunction, inhibited the generation of pro-inflammatory cytokines and reduced myocardial injury in ovariectomized female rats, suggesting a new approach for protecting postmenopausal women against ischaemia-induced myocardial injury. To investigate the putative protective effects of oxytocin or oestrogen receptor agonists against myocardial injury of ovariectomized sedentary or exercised rats, female Sprague-Dawley rats assigned to sham-operated control and ovariectomized (OVX) groups were kept sedentary or undertook swimming exercise for 4 weeks and were treated with saline, an oestrogen receptor (ER) β (DPN) or ERα agonist (PPT) or oxytocin. Ovariectomy increased weight gain and anxiety in sedentary rats, whereas exercise prevented weight gain. When accompanied by exercise, both ER agonists and oxytocin inhibited weight gain and anxiety; oxytocin, in the absence or presence of exercise, increased the left ventricular diastolic dimensions and ejection fraction, whereas ER agonists also increased left ventricular diameter when given to exercised rats. Upon the induction of myocardial ischaemia-reperfusion in the OVX rats, plasma creatine kinase-(muscle-brain) was depressed by PPT and oxytocin, whereas DPN, PPT and OT reduced plasminogen activator inhibitor-1 concentrations. The increased tumour necrosis factor-α concentration in OVX rats was also suppressed by exercise or DPN, PPT or oxytocin treatments, whereas the interleukin-6 concentration was diminished by all the treatments when given in conjunction with exercise. Disorganization of cardiac muscle fibres was reduced in all

  13. Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression

    PubMed Central

    Mah, Linda; Zarate, Carlos A.; Nugent, Allison C.; Singh, Jaskaran B.; Manji, Husseini K.; Drevets, Wayne C.

    2011-01-01

    The D2/D3 receptor agonist pramipexole has clinical efficacy as an antidepressant, but its neural mechanisms are unknown. We used 18FDG-PET to investigate the cerebral metabolic effects of pramipexole augmentation of mood stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7) or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was associated with reductions in normalized metabolism in bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC. Voxel-wise analyses additionally showed decreased normalized metabolism in the left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of the anteromedial PFC following pramipexole treatment. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant action distinct from that previously reported under serotonin reuptake inhibitor treatment and appear compatible with evidence that the central dopaminergic system plays a role in the pathophysiology of bipolar depression. PMID:21029512

  14. Neural mechanisms of antidepressant efficacy of the dopamine receptor agonist pramipexole in treatment of bipolar depression.

    PubMed

    Mah, Linda; Zarate, Carlos A; Nugent, Allison C; Singh, Jaskaran B; Manji, Husseini K; Drevets, Wayne C

    2011-05-01

    The D₂/D₃ receptor agonist pramipexole has clinical efficacy as an antidepressant, but its neural mechanisms are unknown. We used ¹⁸FDG-PET to investigate the cerebral metabolic effects of pramipexole augmentation of mood stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7) or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was associated with reductions in normalized metabolism in bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC. Voxel-wise analyses additionally showed decreased normalized metabolism in the left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of the anteromedial PFC following pramipexole treatment. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant action distinct from that previously reported under serotonin reuptake inhibitor treatment and appear compatible with evidence that the central dopaminergic system plays a role in the pathophysiology of bipolar depression.

  15. Treatment of experimental autoimmune uveoretinitis with peroxisome proliferator-activated receptor α agonist fenofibrate.

    PubMed

    Osada, Miho; Sakai, Tsutomu; Kuroyanagi, Kana; Kohno, Hideo; Tsuneoka, Hiroshi

    2014-01-01

    The peroxisome proliferator-activated receptor α (PPARα) agonist has been approved for treating hypercholesterolemia and lipid abnormalities. Researchers have recently discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. This study aims to investigate the therapeutic effects of fenofibrate on experimental autoimmune uveoretinitis (EAU). EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Fenofibrate was suspended in 3% arabic gum and administered orally at a high dose of 100 mg/kg and at a low dose of 20 mg/kg every day. Fenofibrate treatment was initiated after the clinical onset once daily for 14 days. The rats were examined every other day for clinical signs of EAU. The histological scores and delayed-type hypersensitivity (DTH) were evaluated on day 28 post-immunization. Morphologic and immunohistochemical examinations were performed with light and confocal microscopy, respectively. Lymphocyte proliferation was measured with [3H] thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes. Clinical and histological scores of EAU were decreased in the fenofibrate-treated groups. The expression of inflammatory cytokines and Müller cell proliferation were inhibited in the fenofibrate-treated groups. DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls. The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU. Fenofibrate may be useful for treating intraocular inflammation.

  16. Treatment of experimental autoimmune uveoretinitis with peroxisome proliferator-activated receptor α agonist fenofibrate

    PubMed Central

    Osada, Miho; Kuroyanagi, Kana; Kohno, Hideo; Tsuneoka, Hiroshi

    2014-01-01

    Purpose The peroxisome proliferator-activated receptor α (PPARα) agonist has been approved for treating hypercholesterolemia and lipid abnormalities. Researchers have recently discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. This study aims to investigate the therapeutic effects of fenofibrate on experimental autoimmune uveoretinitis (EAU). Methods EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Fenofibrate was suspended in 3% arabic gum and administered orally at a high dose of 100 mg/kg and at a low dose of 20 mg/kg every day. Fenofibrate treatment was initiated after the clinical onset once daily for 14 days. The rats were examined every other day for clinical signs of EAU. The histological scores and delayed-type hypersensitivity (DTH) were evaluated on day 28 post-immunization. Morphologic and immunohistochemical examinations were performed with light and confocal microscopy, respectively. Lymphocyte proliferation was measured with [3H] thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes. Results Clinical and histological scores of EAU were decreased in the fenofibrate-treated groups. The expression of inflammatory cytokines and Müller cell proliferation were inhibited in the fenofibrate-treated groups. DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls. Conclusions The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU. Fenofibrate may be useful for treating intraocular inflammation. PMID:25489225

  17. Effect of dopamine receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD

    PubMed Central

    Birrell, Mark A; Crispino, Natascia; Hele, David J; Patel, Hema J; Yacoub, Magdi H; Barnes, Peter J; Belvisi, Maria G

    2002-01-01

    Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve-mediated responses.In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D2/3 agonist), ropinirole (D2/3/4 agonist), SKF 38393 (D1/5 agonist), AR-C68397AA (Viozan™) (dual D2/B2 agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR-C68397AA and quinagolide also inhibited depolarization of the human vagus.The quinagolide response was blocked by sulpiride (D2/3 antagonist) but not SCH 23390 (D1/5 antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR-C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus-specific as it inhibited capsaicin-induced depolarization of the rat vagus in a spiperone sensitive manner.In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease. PMID:12055141

  18. Effect of dopamine receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD.

    PubMed

    Birrell, Mark A; Crispino, Natascia; Hele, David J; Patel, Hema J; Yacoub, Magdi H; Barnes, Peter J; Belvisi, Maria G

    2002-06-01

    Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve-mediated responses. In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D(2/3) agonist), ropinirole (D(2/3/4) agonist), SKF 38393 (D(1/5) agonist), AR-C68397AA (Viozan) (dual D(2)/B(2) agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR-C68397AA and quinagolide also inhibited depolarization of the human vagus. The quinagolide response was blocked by sulpiride (D(2/3) antagonist) but not SCH 23390 (D(1/5) antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR-C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus-specific as it inhibited capsaicin-induced depolarization of the rat vagus in a spiperone sensitive manner. In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease.

  19. Identification and optimization of pteridinone Toll-like receptor 7 (TLR7) agonists for the oral treatment of viral hepatitis.

    PubMed

    Roethle, Paul A; McFadden, Ryan M; Yang, Hong; Hrvatin, Paul; Hui, Hon; Graupe, Michael; Gallagher, Brian; Chao, Jessica; Hesselgesser, Joseph; Duatschek, Paul; Zheng, Jim; Lu, Bing; Tumas, Daniel B; Perry, Jason; Halcomb, Randall L

    2013-09-26

    Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.

  20. Theoretical analysis of somatostatin receptor 5 with antagonists and agonists for the treatment of neuroendocrine tumors.

    PubMed

    Nagarajan, Santhosh Kumar; Babu, Sathya; Madhavan, Thirumurthy

    2017-02-02

    We report on SSTR5 receptor modeling and its interaction with reported antagonist and agonist molecules. Modeling of the SSTR5 receptor was carried out using multiple templates with the aim of improving the precision of the generated models. The selective SSTR5 antagonists, agonists and native somatostatin SRIF-14 were employed to propose the binding site of SSTR5 and to identify the critical residues involved in the interaction of the receptor with other molecules. Residues Q2.63, D3.32, Q3.36, C186, Y7.34 and Y7.42 were found to be highly significant for their strong interaction with the receptor. SSTR5 antagonists were utilized to perform a 3D quantitative structure-activity relationship study. A comparative molecular field analysis (CoMFA) was conducted using two different alignment schemes, namely the ligand-based and receptor-based alignment methods. The best statistical results were obtained for ligand-based ([Formula: see text], [Formula: see text] = 0.988, noc = 4) and receptor-guided methods (docked mode 1:[Formula: see text], [Formula: see text], noc = 5), (docked mode 2:[Formula: see text] = 0.555, [Formula: see text], noc = 5). Based on CoMFA contour maps, an electropositive substitution at [Formula: see text], [Formula: see text] and [Formula: see text] position and bulky group at [Formula: see text] position are important in enhancing molecular activity.

  1. Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

    PubMed Central

    Mosińska, Paula; Zatorski, Hubert; Storr, Martin; Fichna, Jakub

    2017-01-01

    There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients’ quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation. PMID:28238253

  2. Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience.

    PubMed

    Grosshans, Martin; Mutschler, Jochen; Kiefer, Falk

    2015-07-01

    The treatment of cocaine dependence is difficult as no approved pharmacotherapy is available as yet. However, in preclinical and clinical trials, a variety of compounds were tested for suitability as inhibitors of craving for and relapse into the use of cocaine, among these antidepressants, antiepileptics, dopamine agonists, disulfiram, and naltrexone. Nalmefene, a structural derivative of naltrexone, shares with its parent compound approval (granted by the European Medical Agency in 2013) as a medication for the treatment of alcohol addiction in the European Union. It differs from naltrexone by a higher affinity for the δ opioid-receptors and a partial agonistic affinity to the κ opioid-receptors. It should be noted that patients addicted to cocaine show a considerable increase in κ receptors in the nucleus accumbens. This report describes the case of an abstinent cocaine-addicted patient regularly afflicted with cravings for cocaine. The patient took as-needed nalmefene for 5 months whenever she developed a craving for cocaine. For most of these interventions, the patient reported an abatement of craving and could avoid relapsing into cocaine consumption. This effect may be accounted for by nalmefene acting, other than naltrexone, as a partial agonist of the κ opioid-receptors. Therefore, nalmefene might be a promising new option in the pharmacological repertoire for the treatment of cocaine addiction.

  3. Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka; Spiteller, Michael

    2012-12-01

    The relationship between the molecular structure and physical properties of functionalized naturally occurred Ergot-alkaloids as potential dopamine D3 receptor agonists is presented. The molecular modeling of the ergoline-skeleton is based on the comprehensive theoretical study of the binding affinity of the isolated chemicals towards the active sites of the D3 sub-type receptor (D3R) loops. The studied proton accepting ability under physiological conditions allows classifying four types of monocationics, characterizing with the different binding modes to D3R involving selected amino acid residues to the active sites. These results marked the pharmaceutical potential and clinical usage of the reported compounds as antipsychotic drugs for Schizophrenia treatment, since they allowed evaluating the highlights of the different hypothesizes of the biochemical causes the illness. The applied complex approach for theoretical and experimental elucidation, including quantum chemistry method, electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometric (MS) methods, nuclear magnetic resonance and vibrational IR and Raman spectroscopy on the isolated fifteen novel derivatives (1)-(15) and their different protonated forms (1a)-(15a) evidenced a strong dependence of molecular conformation, physical properties and binding affinity. Thus, the semi-synthetic functionalization of the naturally occurred products (NPs), provided significant possibilities to further molecular drugs-design and development of novel derivatives with wanted biological function, using the established profile of selected classes/families of NPs. The work described chiefly the non-linear (NL) approach for the interpretation of the mass chromatograms on the performed hybrid high performance liquid chromatography (HPLC) tandem MS/MS and MS/MS/MS experiments, discussing the merits and great diversity of instrumentation flexibility, thus achieving fundamental

  4. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease.

    PubMed

    Sahebkar, Amirhossein; Chew, Gerard T; Watts, Gerald F

    2014-03-01

    Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects. This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD). ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

  5. [Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes].

    PubMed

    Salvador, Javier; Andrada, Patricia

    2014-09-01

    The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  6. Effects of Long-Term Treatment with Estradiol and Estrogen Receptor Subtype Agonists on Serotonergic Function in Ovariectomized Rats.

    PubMed

    Benmansour, Saloua; Adeniji, Opeyemi S; Privratsky, Anthony A; Frazer, Alan

    2016-01-01

    Acute estradiol treatment was reported to slow the clearance of serotonin via activation of estrogen receptors (ER)β and/or GPR30 and to block the ability of a selective serotonin reuptake inhibitor (SSRI) to slow serotonin clearance via activation of ERα. In this study, the behavioral consequences of longer-term treatments with estradiol or ER subtype-selective agonists and/or an SSRI were examined in the forced swim test (FST). Ovariectomized rats were administered the following for 2 weeks: estradiol, ERβ agonist (diarylpropionitrile, DPN), GPR30 agonist (G1), ERα agonist (PPT), and/or the SSRI sertraline. Similar to sertraline, longer-term treatment with estradiol, DPN or G1 induced an antidepressant-like effect. By contrast, PPT did not, even though it blocked the antidepressant-like effect of sertraline. Uterus weights, used as a peripheral measure of estrogenic activity, were increased by estradiol and PPT but not DPN or G1 treatment. A second part of this study investigated, using Western blot analyses in homogenates from hippocampus, whether these behavioral effects are accompanied by changes in the activation of specific signaling pathways and/or TrkB. Estradiol and G1 increased phosphorylation of Akt, ERK and TrkB. These effects were similar to those obtained after treatment with sertraline. Treatment with DPN increased phosphorylation of ERK and TrkB, but it did not alter that of Akt. Treatment with PPT increased phosphorylation of Akt and ERK without altering that of TrkB. In conclusion, activation of at least TrkB and possibly ERK may be involved in the antidepressant-like effect of estradiol, ERβ and GPR30 agonists whereas Akt activation may not be necessary. © 2015 S. Karger AG, Basel.

  7. EFFECTS OF LONG-TERM TREATMENT WITH ESTRADIOL AND ESTROGEN RECEPTOR SUBTYPE AGONISTS ON SEROTONERGIC FUNCTION IN OVARIECTOMIZED RATS

    PubMed Central

    Benmansour, Saloua; Adeniji, Opeyemi S.; Privratsky, Anthony A.; Frazer, Alan

    2015-01-01

    Acute estradiol treatment was reported to slow the clearance of serotonin via activation of estrogen receptors (ER)β and/or GPR30 and to block the ability of a selective serotonin reuptake inhibitor (SSRI) to slow serotonin clearance via activation of ERα. In this study, the behavioral consequences of longer-term treatments with estradiol or ER subtype-selective agonists and/or an SSRI were examined in the forced swim test (FST). Ovariectomized rats were administered for two weeks: estradiol, ERβ agonist (DPN), GPR30 agonist (G1), ERα agonist (PPT), and/or the SSRI sertraline. Similar to sertraline, longer-term treatment with estradiol, DPN or G1 induced an antidepressant- like effect. By contrast, PPT did not, even though it blocked the antidepressant-like effect of sertraline. Uterus weights, used as a peripheral measure of estrogenic activity, were increased by estradiol and PPT but not DPN or G1 treatment. A second part of this study investigated, using Western blot analyses in homogenates from hippocampus, whether these behavioral effects are accompanied by changes in the activation of specific signaling pathways and/or TrkB. Estradiol and G1 increased phosphorylation of Akt, ERK and TrkB. These effects were similar to those obtained after treatment with sertraline. Treatment with DPN increased phosphorylation of ERK and TrkB but it did not alter that of Akt. Treatment with PPT increased phosphorylation of Akt and ERK without altering that of TrkB. In conclusion, activation of at least TrkB and possibly ERK may be involved in the antidepressant-like effect of estradiol, ERβ and GPR30 agonists whereas Akt activation may not be necessary. PMID:26159182

  8. Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments.

    PubMed

    Metzger, Joseph M; Gagen, Karen; Raustad, Kate A; Yang, Liming; White, Amanda; Wang, Sheng-Ping; Craw, Stephanie; Liu, Ping; Lanza, Thomas; Lin, Linus S; Nargund, Ravi P; Guan, Xiao-Ming; Strack, Alison M; Reitman, Marc L

    2010-11-01

    Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (T(b)) is regulated in part by nutritional status, with a reduced T(b) during fasting. We report that fed Brs3 knockout mice have a lower T(b), which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased T(b), more so when the baseline T(b) was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the T(b) increase attenuated despite continued weight loss efficacy. The increase in T(b) was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a β-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting T(b) reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, β₃-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted T(b) and the fasted, resting metabolic rates. The T(b) assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery.

  9. Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists

    PubMed Central

    Murányi, Marianna; Cinar, Resat; Kékesi, Orsolya; Birkás, Erika; Fábián, Gabriella; Bozó, Beáta; Zentai, András; Tóth, Géza; Kicsi, Emese Gabriella; Mácsai, Mónika; Szabó, Gyula; Szücs, Mária

    2013-01-01

    Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”. PMID:24350273

  10. Ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists.

    PubMed

    Murányi, Marianna; Cinar, Resat; Kékesi, Orsolya; Birkás, Erika; Fábián, Gabriella; Bozó, Beáta; Zentai, András; Tóth, Géza; Kicsi, Emese Gabriella; Mácsai, Mónika; Dochnal, Roberta; Szabó, Gyula; Szücs, Mária

    2013-01-01

    Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity".

  11. P2Y2 receptor agonists for the treatment of dry eye disease: a review.

    PubMed

    Lau, Oliver C F; Samarawickrama, Chameen; Skalicky, Simon E

    2014-01-01

    Recent advances in the understanding of dry eye disease (DED) have revealed previously unexplored targets for drug therapy. One of these drugs is diquafosol, a uridine nucleotide analog that is an agonist of the P2Y2 receptor. Several randomized controlled trials have demonstrated that the application of topical diquafosol significantly improves objective markers of DED such as corneal and conjunctival fluorescein staining and, in some studies, tear film break-up time and Schirmer test scores. However, this has been accompanied by only partial improvement in patient symptoms. Although evidence from the literature is still relatively limited, early studies have suggested that diquafosol has a role in the management of DED. Additional studies would be helpful to delineate how different subgroups of DED respond to diquafosol. The therapeutic combination of diquafosol with other topical agents also warrants further investigation.

  12. Tasimelteon (Hetlioz™): A New Melatonin Receptor Agonist for the Treatment of Non-24-Hour Sleep-Wake Disorder.

    PubMed

    Bonacci, Janene M; Venci, Jineane V; Gandhi, Mona A

    2015-10-01

    In January 2014, the US Food and Drug Administration approved tasimelteon (Hetlioz™), a melatonin-receptor agonist for the treatment of non-24-hour sleep-wake disorder. This article provides an overview of the mechanism of action, pharmacokinetic properties, as well as the clinical efficacy, safety, and tolerability of tasimelteon. Relevant information was identified through a comprehensive literature search of several databases using the key words tasimelteon, Non-24-hour Sleep-Wake disorder, Non-24, and melatonin. Further information was obtained from the tasimelteon package insert, fda.gov, clinicaltrials.gov, briefing materials provided by Vanda Pharmaceuticals, and posters from scientific meetings. © The Author(s) 2014.

  13. Virtual screening studies of Chinese medicine Coptidis Rhizoma as alpha7 nicotinic acetylcholine receptor agonists for treatment of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Xiang, Li; Xu, Youdong; Zhang, Yan; Meng, Xianli; Wang, Ping

    2015-04-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine CoptidisRhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from CoptidisRhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein-ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

  14. Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

    PubMed Central

    2010-01-01

    Background Liver × receptor α (LXRα) and β (LXRβ) are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), tumor necrosis factor-α, (TNF-α) and interleukin-1β (IL-1β). Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression) in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases. PMID:20175894

  15. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.

    PubMed

    Alig, Leo; Alsenz, Jochem; Andjelkovic, Mirjana; Bendels, Stefanie; Bénardeau, Agnès; Bleicher, Konrad; Bourson, Anne; David-Pierson, Pascale; Guba, Wolfgang; Hildbrand, Stefan; Kube, Dagmar; Lübbers, Thomas; Mayweg, Alexander V; Narquizian, Robert; Neidhart, Werner; Nettekoven, Matthias; Plancher, Jean-Marc; Rocha, Cynthia; Rogers-Evans, Mark; Röver, Stephan; Schneider, Gisbert; Taylor, Sven; Waldmeier, Pius

    2008-04-10

    The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.

  16. AZD3480, a novel nicotinic receptor agonist, for the treatment of attention-deficit/hyperactivity disorder in adults.

    PubMed

    Potter, Alexandra S; Dunbar, Geoffrey; Mazzulla, Emily; Hosford, David; Newhouse, Paul A

    2014-02-01

    Laboratory studies have found that acute stimulation of nicotinic acetylcholine receptors improves cognition in adult attention-deficit/hyperactivity disorder (ADHD). Clinical trials of nicotinic agonists have been mixed, underscoring the need to understand the mechanisms for individual differences in clinical response. Using cognitive models within a clinical trial framework may provide insight into these differences. This was a within-subjects, randomized, placebo-controlled double-blind trial of the nicotinic agonist AZD3480 (also termed TC-1734) at doses of 5 mg and 50 mg and placebo in adults with ADHD. The order of the 2-week treatment periods was randomized, and a 3-week wash out separated each drug treatment period. Response inhibition (Stop Signal Task [SST]) and clinical efficacy (Investigator Rated Conners Adult ADHD Rating Scale [CAARS-INV]) were the a priori primary outcome measures of cognitive and clinical effects. We hypothesized that AZD3480 treatment would improve SST performance and clinical symptoms (CAARS-INV Total ADHD Symptoms Score). Thirty subjects were randomized, with 24 included in the intent-to-treat analyses. SST performance and total ADHD symptoms were significantly improved with 50 mg of AZD3480. CAARS-INV ratings of inattention, memory problems, and emotional lability/impulsivity were significantly improved with 50 mg of AZD3480. These results support previous work suggesting that nicotinic agonists are viable as treatments for adult ADHD. Measuring cognitive endophenotypes related to both the disorder and mechanism of treatment may help further rational drug development for dimensional features that cross-cut psychiatric disorders. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism.

    PubMed

    Moskal, Joseph R; Burgdorf, Jeffrey; Kroes, Roger A; Brudzynski, Stefan M; Panksepp, Jaak

    2011-10-01

    Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-cycloserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism. We dedicate this paper to Ole Ivar Lovaas (May 8, 1927-August 2, 2010), a pioneer in the field of autism. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. In vivo pharmacological characterization of AC-3933, a benzodiazepine receptor partial inverse agonist for the treatment of Alzheimer's disease.

    PubMed

    Hatayama, Y; Hashimoto, T; Kohayakawa, H; Kiyoshi, T; Nakamichi, K; Kinoshita, T; Yoshida, N

    2014-04-18

    GABAergic neurons are known to inhibit neural transduction and therefore negatively affect excitatory neural circuits in the brain. We have previously reported that 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1,6-naphthyridin-2(1H)-one (AC-3933), a partial inverse agonist for the benzodiazepine receptor (BzR), reverses GABAergic inhibitory effect on cholinergic neurons, and thus enhances acetylcholine release from these neurons in rat hippocampal slices. In this study, we evaluated AC-3933 potential for the treatment of Alzheimer's disease, a disorder characterized by progressive decline mainly in cholinergic function. Oral administration of AC-3933 (0.01-0.03mg/kg) resulted in the amelioration of scopolamine-induced amnesia, as well as a shift in electroencephalogram (EEG) relative power characteristic of pro-cognitive cholinergic activators, such as donepezil. In addition, treatment with AC-3933 even at the high dose of 100mg/kg p.o. produced no seizure or anxiety, two major adverse effects of BzR inverse agonists developed in the past. These findings indicate that AC-3933 with its low risk for side effects may be useful in the treatment of Alzheimer's disease.

  19. Fates of endocytosed somatostatin sst2 receptors and associated agonists.

    PubMed Central

    Koenig, J A; Kaur, R; Dodgeon, I; Edwardson, J M; Humphrey, P P

    1998-01-01

    Somatostatin agonists are rapidly and efficiently internalized with the somatostatin sst2 receptor. The fate of internalized agonists and receptors is of critical importance because the rate of ligand recycling back to the cell surface can limit the amount of radioligand accumulated inside the cells, whereas receptor recycling might be of vital importance in providing the cell surface with dephosphorylated, resensitized receptors. Furthermore the accumulation of radioisotope-conjugated somatostatin agonists inside cancer cells resulting from receptor-mediated internalization has been used as a treatment for cancers that overexpress somatostatin receptors. In the present study, radio-iodinated agonists at the sst2 somatostatin receptor were employed to allow quantitative analysis of the fate of endocytosed agonist. After endocytosis, recycling back to the cell surface was the main pathway for both 125I-labelled somatostatin-14 (SRIF-14) and the more stable agonist 125I-labelled cyclo(N-Me-Ala-Tyr-d-Trp-Lys-Abu-Phe) (BIM-23027; Abu stands for aminobutyric acid), accounting for 75-85% of internalized ligand when re-endocytosis of radioligand was prevented. We have shown that there is a dynamic cycling of both somatostatin agonist ligands and receptors between the cell surface and internal compartments both during agonist treatment and after surface-bound agonist has been removed, unless steps are taken to prevent the re-activation of receptors by recycled agonist. Internalization leads to increased degradation of 125I-labelled SRIF-14 but not 125I-labelled BIM-23027. The concentration of recycled agonist accumulating in the extracellular medium was sufficient to re-activate the receptor, as measured both by the inhibition of forskolin-stimulated adenylate cyclase and the recovery of surface receptor number after internalization. PMID:9820803

  20. Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis*

    PubMed Central

    Lima, Emerson de Andrade; Lima, Mariana Modesto Dantas de Andrade; Marques, Cláudia Diniz Lopes; Duarte, Angela Luzia Branco Pinto; Pita, Ivan da Rocha; Pita, Maira Galdino da Rocha

    2013-01-01

    Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis. PMID:24474126

  1. Screening of agonistic activities against four nuclear receptors in wastewater treatment plants in Japan using a yeast two-hybrid assay.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Matsui, Hisae; Sei, Kazunari; Nakanishi, Tsuyoshi; Ike, Michihiko

    2011-01-01

    To assess the potential endocrine disruptive effects through multiple nuclear receptors (NRs), especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs (estrogen receptor alpha, thyroid hormone receptor alpha, retinoic acid receptor alpha and retinoid X receptor alpha) of untreated and treated wastewater from municipal wastewater treatment plants (WWTPs) in Japan using a yeast two-hybrid assay. Investigation of the influent and effluent of seven WWTPs revealed that agonistic activities against steroidal and non-steroidal NRs were always detected in the influents and partially remained in the effluents. Further investigation of four WWTPs employing conventional activated sludge, pseudo-anoxic-oxic, anoxic-oxic and anaerobic-anoxic-oxic processes revealed that the ability to reduce the agonistic activity against each of the four NRs varies depending on the treatment process. These results indicated that municipal wastewater in Japan commonly contains endocrine disrupting chemicals that exert agonistic activities on steroidal and non-steroidal NRs, and that some of these chemicals are released into the natural aquatic environment. Although the results obtained in yeast assays suggested that measured levels of non-steroidal NR agonists in the effluent of WWTPs were not likely to cause any biological effect, further study is required to assess their possible risks in detail.

  2. Agonists for the Chemokine Receptor CXCR4

    PubMed Central

    2011-01-01

    The development of agonists for the chemokine receptor CXCR4 could provide promising therapeutic candidates. On the basis of previously forwarded two site model of chemokine–receptor interactions, we hypothesized that linking the agonistic N-terminus of SDF-1 to the T140 backbone would yield new high-affinity agonists of CXCR4. We developed chimeras with the agonistic SDF-1 N-terminus grafted to a T140 side chain and tested their binding affinity and chemotactic agonist activity. While chimeras with the peptide grafted onto position 12 of T140 remained high-affinity antagonists, those bearing the peptide on position 14 were in part agonists. One chimera was a full CXCR4 agonist with 25 nM affinity, and several chimeras showed low nanomolar affinities with partial agonist activity. Our results confirmed that we have developed high-affinity agonists of CXCR4. PMID:21841963

  3. Dopamine receptor agonists, partial agonists and psychostimulant addiction.

    PubMed

    Pulvirenti, L; Koob, G F

    1994-10-01

    Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

  4. A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment.

    PubMed

    Pei, Yue; Asif-Malik, Aman; Hoener, Marius; Canales, Juan J

    2016-05-19

    Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and psychostimulant action. Several selective TAAR1 agonists have previously shown efficacy in models of cocaine addiction. However, the effects of TAAR1 activation on methamphetamine (METH)-induced behaviours are less well understood, as indeed are the underlying neurochemical mechanisms mediating potential interactions between TAAR1 and METH. Here, in a progressive ratio schedule of reinforcement the partial TAAR1 agonist, RO5263397, reduced the break-point for METH self-administration, while significantly increasing responding maintained by food reward. Following self-administration and extinction training, RO5263397 completely blocked METH-primed reinstatement of METH seeking. Moreover, when used as a substitute, unlike a low dose of METH, which sustained vigorous responding when substituting for the training dose of METH, RO5263397 was not self-administered at any dose, thus exhibiting no apparent abuse liability. Fast-scan cyclic voltammetry experiments showed that RO5263397 prevented METH-induced DA overflow in slices of the nucleus accumbens, while having no effect on DA transmission in its own right. Collectively, the present observations demonstrate that partial TAAR1 activation decreases the motivation to self-administer METH, blocks METH-primed reinstatement of METH seeking and prevents METH-induced DA elevations in the nucleus accumbens, and strongly support the candidacy of TAAR1-based medications as potential substitute treatment in METH addiction.

  5. Neonatal DSP-4 treatment modifies antinociceptive effects of the CB1 receptor agonist methanandamide in adult rats.

    PubMed

    Korossy-Mruk, Eva; Kuter, Katarzyna; Nowak, Przemysław; Szkilnik, Ryszard; Rykaczewska-Czerwinska, Monika; Kostrzewa, Richard M; Brus, Ryszard

    2013-01-01

    To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB(1)-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc × 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB(1) receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB(1) receptor density in the brain.

  6. Evolution of peroxisome proliferator-activated receptor agonists.

    PubMed

    Chang, Feng; Jaber, Linda A; Berlie, Helen D; O'Connell, Mary Beth

    2007-06-01

    To discuss the evolution of peroxisome proliferator-activated receptor (PPAR) agonists from single site to multiple subtype or partial agonists for the treatment of type 2 diabetes, dyslipidemia, obesity, and the metabolic syndrome. Information was obtained from MEDLINE (1966-March 2007) using search terms peroxisome proliferator-activated receptor agonist, PPAR dual agonist, PPAR alpha/gamma agonist, PPAR pan agonist, partial PPAR, and the specific compound names. Other sources included pharmaceutical companies, the Internet, and the American Diabetes Association 64th-66th Scientific Sessions abstract books. Animal data, abstracts, clinical trials, and review articles were reviewed and summarized. PPAR alpha, gamma, and delta receptors play an important role in lipid metabolism, regulation of adipocyte proliferation and differentiation, and insulin sensitivity. The PPAR dual agonists were developed to combine the triglyceride lowering and high-density lipoprotein cholesterol elevation from the PPAR-alpha agonists (fibrates) with the insulin sensitivity improvement from the PPAR-gamma agonists (thiazolidinediones). Although the dual agonists reduced hemoglobin A(1C) (A1C) and improved the lipid profile, adverse effects led to discontinued development. Currently, PPAR-delta agonists (GW501516 in Phase I trials), partial PPAR-gamma agonists (metaglidasen in Phase II and III trials), and pan agonists (alpha, gamma, delta; netoglitazone in Phase II and III trials) with improved cell and tissue selectivity are undergoing investigation to address multiple aspects of the metabolic syndrome with a single medication. By decreasing both A1C and triglycerides, metaglidasen did improve multiple aspects of the metabolic syndrome with fewer adverse effects than compared with placebo. Metaglidasen is now being compared with pioglitazone. Influencing the various PPARs results in improved glucose, lipid, and weight management, with effects dependent on full or partial agonist

  7. Transdermal delivery of dopamine receptor agonists.

    PubMed

    Reichmann, Heinz

    2009-12-01

    Conceptually, continuous dopaminergic stimulation is universally accepted to be the preferred therapeutic strategy to prevent or postpone dyskinesia in Parkinson's disease (PD). L-dopa has a short half-life of 2 hours and causes dyskinesia, whereas dopamine receptor agonists usually have a much longer half-life. Of the latter agents, cabergoline has the longest half-life of 68 hours and is ideal for the prevention of dyskinesia; but this is also true for other dopamine receptor agonists such as ropinirole or pramipexole, which have a shorter half-life of about 6-8 hours. Due to the possible development of valvular fibrosis, cabergoline is, however, only approved as a second-line treatment in PD, and patch technology has therefore gained major interest. So far, rotigotine is the only dopamine receptor agonist available as a patch. There is good evidence that once-daily patch usage provides patients with constant dopaminergic stimulation, and that patches are of equal potency to other oral non-ergot derivatives such as ropinirole and pramipexole. The disadvantages of patches are skin irritation and crystallization of the drug if not kept in the refrigerator. Copyright 2009 Elsevier Ltd. All rights reserved.

  8. Regulation of cannabinoid CB2 receptor constitutive activity in vivo: repeated treatments with inverse agonists reverse the acute activation of JNK and associated apoptotic signaling in mouse brain.

    PubMed

    Salort, Glòria; Álvaro-Bartolomé, María; García-Sevilla, Jesús A

    2017-03-01

    CB2 receptors express constitutive activity and inverse agonists regulate receptor basal activity, which might be involved in death mechanisms. This study assessed the effects of a selective CB2 agonist (JWH133) and different CB2 inverse agonists (AM630, JTE907, raloxifene) on death pathways in brain. The acute (JWH13) and the acute/chronic effects (AM630, JTE907, raloxifene) of CB2 ligands regulating pro-apoptotic c-Jun NH2-terminal kinase (p-JNK/JNK ratio) and associated signaling of extrinsic (Fas receptor, Fas-Associated death domain protein, FADD) and intrinsic (Bax, cytochrome c) death pathways (nuclear poly (ADP-ribose) polymerase PARP) were investigated in mouse brain. Mice were treated with CB2 drugs and target protein contents were assessed by western blot analysis. JWH133 reduced cortical JNK (-27-45%) whereas AM630 acutely increased JNK in cortex (+61-148%), cerebellum (+34-40%), and striatum (+33-42%). JTE907 and raloxifene also increased cortical JNK (+31%-57%). Acute AM630, but not JWH133, increased cortical FADD, Bax, cytochrome c, and PARP cleavage. Repeated treatments with the three CB2 inverse agonists were associated with a reversal of the acute effects resulting in decreases in cortical JNK (AM630: -36%; JTE907: -25%; raloxifene: -11%). Chronic treatments also induced a reversal with down-regulation (AM630) or only tolerance (JTE907 and raloxifene) on other apoptotic markers (FADD, Bax, cytochrome c, PARP). AM630 and JTE907 are CB2 protean ligands. Thus, chronic inverse agonists abolished CB2 constitutive activity and then the ligands behaved as agonists reducing (like JWH133) JNK activity. Acute and chronic treatments with CB2 inverse agonists regulate in opposite directions brain death markers.

  9. The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia

    PubMed Central

    Gill, Kathryn M.; Grace, Anthony A.

    2014-01-01

    Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity. PMID:24345268

  10. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  11. Treatment of antipsychotic-induced hyperprolactinemia: an update on the role of the dopaminergic receptors D2 partial agonist aripiprazole.

    PubMed

    De Berardis, Domenico; Fornaro, Michele; Serroni, Nicola; Marini, Stefano; Piersanti, Monica; Cavuto, Marilde; Valchera, Alessandro; Mazza, Monica; Girinelli, Gabriella; Iasevoli, Felice; Perna, Giampaolo; Martinotti, Giovanni; Di Giannantonio, Massimo

    2014-01-01

    Hyperprolactinemia is an unwanted adverse effect present in several typical and atypical antipsychotics. Aripiprazole is a drug with partial agonist activity at the level of dopamine receptors D2, which may be effective for antipsychotic- induced hyperprolactinemia. Therefore, we analyzed the literature concerning the treatment of antipsychoticinduced hyperprolactinemia with aripiprazole by updating a previous paper written on the same topic. More recent studies were reviewed. They showed that there are two options for the treatment of antipsychotic-induced hyperprolactinemia with aripiprazole. The safest strategy may require the addition of aripiprazole to ongoing treatments, in the case patients had previously responded to antipsychotic drugs and then developed hyperprolactinemia. However, it is advisable to monitor the patients in case relapses and/or side effect, although rare, might occur. Switching drugs should be considered when a patient does not appear to be responding to the previous antipsychotic, thus developing hyperprolactinemia. A cross-taper switch should always be considered, but the risk of a relapse in the disorder may occur more frequently and the patients should be closely monitored. However, limitations must be considered and further studies are needed to definitely elucidate this important issue. Some relevant patents are also described in this review.

  12. Effects of a combined treatment with tamoxifen and estrogen receptor β agonists on human breast cancer cell lines.

    PubMed

    Lattrich, Claus; Schüler, Susanne; Häring, Julia; Skrzypczak, Maciej; Ortmann, Olaf; Treeck, Oliver

    2014-01-01

    Coexpression of estrogen receptors (ER) α and β is present in about half of all breast cancer cases. Whereas ERα is a well-established target for endocrine therapy with the selective estrogen receptor modulator tamoxifen, the applicability of ERβ as target in breast cancer therapy is unclear. In this study, we examined the effects of two synthetic ERβ agonists alone and in combination with tamoxifen on ERα/β-positive breast cancer cells. We treated MCF-7 and T-47D breast cancer cells with the ERβ agonists ERB-041 and WAY-200070 and measured the effects on cell growth. In addition, transcriptome analyses were performed by means of Affymetrix GeneChip arrays. When given alone, ERβ agonists ERB-041 and WAY-200070 did not affect the growth of MCF-7 or T-47D cells. In contrast, addition of these drugs to tamoxifen increased its growth-inhibitory effect on both cell lines. This effect was more pronounced under serum-free conditions, but was also observed in the presence of serum in T-47D cells. Transcriptome analyses revealed a set of genes regulated after addition of ERβ agonists including S100A8 and CD177. The observed enhanced growth-inhibitory effects of a combination of tamoxifen and ERβ agonists in vitro encourage further studies to test its possible use in the clinical setting.

  13. Long-Term Estrogen Receptor Beta Agonist Treatment Modifies the Hippocampal Transcriptome in Middle-Aged Ovariectomized Rats

    PubMed Central

    Sárvári, Miklós; Kalló, Imre; Hrabovszky, Erik; Solymosi, Norbert; Rodolosse, Annie; Liposits, Zsolt

    2016-01-01

    Estradiol (E2) robustly activates transcription of a broad array of genes in the hippocampal formation of middle-aged ovariectomized rats via estrogen receptors (ERα, ERβ, and G protein-coupled ER). Selective ERβ agonists also influence hippocampal functions, although their downstream molecular targets and mechanisms are not known. In this study, we explored the effects of long-term treatment with ERβ agonist diarylpropionitrile (DPN, 0.05 mg/kg/day, sc.) on the hippocampal transcriptome in ovariectomized, middle-aged (13 month) rats. Isolated hippocampal formations were analyzed by Affymetrix oligonucleotide microarray and quantitative real-time PCR. Four hundred ninety-seven genes fulfilled the absolute fold change higher than 2 (FC > 2) selection criterion. Among them 370 genes were activated. Pathway analysis identified terms including glutamatergic and cholinergic synapse, RNA transport, endocytosis, thyroid hormone signaling, RNA degradation, retrograde endocannabinoid signaling, and mRNA surveillance. PCR studies showed transcriptional regulation of 58 genes encoding growth factors (Igf2, Igfb2, Igf1r, Fgf1, Mdk, Ntf3, Bdnf), transcription factors (Otx2, Msx1), potassium channels (Kcne2), neuropeptides (Cck, Pdyn), peptide receptors (Crhr2, Oprm1, Gnrhr, Galr2, Sstr1, Sstr3), neurotransmitter receptors (Htr1a, Htr2c, Htr2a, Gria2, Gria3, Grm5, Gabra1, Chrm5, Adrb1), and vesicular neurotransmitter transporters (Slc32a1, Slc17a7). Protein-protein interaction analysis revealed networking of clusters associated with the regulation of growth/troph factor signaling, transcription, translation, neurotransmitter and neurohormone signaling mechanisms and potassium channels. Collectively, the results reveal the contribution of ERβ-mediated processes to the regulation of transcription, translation, neurogenesis, neuromodulation, and neuroprotection in the hippocampal formation of ovariectomized, middle-aged rats and elucidate regulatory channels responsible for

  14. Predictors of weight-loss response with glucagon-like peptide-1 receptor agonist treatment among adolescents with severe obesity.

    PubMed

    Nathan, B M; Rudser, K D; Abuzzahab, M J; Fox, C K; Coombes, B J; Bomberg, E M; Kelly, A S

    2016-02-01

    In two previous, separate clinical trials, we demonstrated significant reductions in body mass index (BMI) with exenatide in adolescents with severe obesity. In the present study, we pooled data from these near identical trials to evaluate factors that may predict BMI reduction at 3 months. Data from 32 patients (mean age 14.3 ± 2.2 years; 69% female; mean BMI 39.8 ± 5.8 kg m(-2)) were included. Exenatide treatment consisted of 5 mcg twice daily for 1 month, followed by an increase to 10 mcg twice daily for 2 additional months. Predictor variables included baseline BMI, BMI percent change at 1 month, incidence of nausea or vomiting and baseline appetite and satiety measures. Treatment effects of percent change in BMI from baseline were estimated within predictor subgroups using generalized estimating equations with exchangeable working correlation and robust variance estimation for confidence intervals and P-values to account for paired observations. The pooled data treatment effect on absolute BMI at 3 months was -3.42% (95% confidence interval: -5.41%, -1.42%) compared to placebo. Within treated participants, appetite at baseline (treatment effect in high [-4.28%] vs. low [1.02%], P = 0.028) and sex (treatment effect in female [-4.78%] vs. male [0.76%], P = 0.007) were significant predictors of change in BMI at 3 months. Baseline BMI, BMI percent change at 1 month, age, incidence of nausea, vomiting, or other gastrointestinal symptoms and satiety scores did not predict 3-month responses. Sex and measures of appetite may serve as useful predictors of glucagon-like peptide-1 receptor agonist treatment response among adolescents with severe obesity.

  15. Frovatriptan: a selective type 1B/1D serotonin receptor agonist for the treatment of migraine headache.

    PubMed

    Cole, Patrick; Rabasseda, Xavier

    2002-09-01

    Frovatriptan belongs to an innovative family of compounds aimed at breaking through the long-standing barrier of migraine headache understanding and treatment. While a typology of headaches has been recognized for some time, and a number of therapies have been introduced for reduction of headache pain and duration, the causes of migraine remain a subject of debate. Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation. Frovatriptan, like all the triptans, acts by inducing vasoconstriction of the meningeal arteries. It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin 5-HT1B/1D receptors. Frovatriptan has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials, which have also indicated that dose adjustments for age or gender are not necessary for the drug. Patients have found the use of frovatriptan acceptable over the long-term, and overall a low-incidence of adverse effects has been reported. Though not a prophylactic, frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine. Copyright 2002 Prous Science

  16. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's Disease.

    PubMed

    Stachel, Shawn J; Zerbinatti, Celina; Rudd, Michael T; Cosden, Mali; Suon, Sokreine; Nanda, Kausik K; Wessner, Keith; DiMuzio, Jillian; Maxwell, Jill; Wu, Zhenhua; Uslaner, Jason M; Michener, Maria S; Szczerba, Peter; Brnardic, Edward; Rada, Vanessa; Kim, Yuntae; Meissner, Robert; Wuelfing, Peter; Yuan, Yang; Ballard, Jeanine; Holahan, Marie; Klein, Daniel J; Lu, Jun; Fradera, Xavier; Parthasarathy, Gopal; Uebele, Victor N; Chen, Zhongguo; Li, Yingjie; Li, Jian; Cooke, Andrew J; Bennett, D Jonathan; Bilodeau, Mark T; Renger, John

    2016-04-14

    Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.

  17. Histamine H3-receptor inverse agonists as novel antipsychotics.

    PubMed

    Ito, Chihiro

    2009-06-01

    Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

  18. The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.

    PubMed

    Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G

    2011-01-13

    β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

  19. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  20. Kappa Opioid Receptor Agonist and Brain Ischemia.

    PubMed

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury.

  1. Alpha2-adrenergic receptor agonists as analgesics.

    PubMed

    Boyd, R E

    2001-08-01

    Alpha2-adrenergic receptor agonists are analgesic agents, and the alpha2-adrenergic agonist clonidine has been used in clinical studies for regional analgesia after intrathecal administration. We review here recent developments concerning the structure activity relationships of a new class of potent alpha2-adrenergic agonists and their use as analgesic agents. The effect of structure upon cardiovascular side-effects is also monitored, such as the prolongation of the QT portion of the cardiac action potential.

  2. In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis.

    PubMed

    McBride, Andrew; Hoy, Anna M; Bamford, Mark J; Mossakowska, Danuta E; Ruediger, Martin P; Griggs, Jeremy; Desai, Sapna; Simpson, Kate; Caballero-Hernandez, Ivan; Iredale, John P; Pell, Theresa; Aucott, Rebecca L; Holmes, Duncan S; Webster, Scott P; Fallowfield, Jonathan A

    2017-09-07

    The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery.

  3. Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals

    PubMed Central

    2011-01-01

    Background Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP) and congestive heart failure (CHF) as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R) agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting. Hypothesis We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals. Methods We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP. Results In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL) force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals. Conclusions These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production. PMID:21235761

  4. α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

    PubMed Central

    Toyohara, Jun; Hashimoto, Kenji

    2010-01-01

    Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs. PMID:21249164

  5. Apparent histological changes of adipocytes after treatment with CL 316,243, a β-3-adrenergic receptor agonist.

    PubMed

    Ghorbani, Masoud; Teimourian, Shahram; Farzad, Reza; Asl, Nabiollah Namvar

    2015-01-01

    The objective of this experiment was to study the effect of CL 316,243 (CL) (a highly selective β3-adrenergic receptor agonist) on cellular changes occurring in retroperitoneal white adipose tissue (RWAT) of lean and obese rats. Ten-month-old lean and obese Zucker rats were implanted subcutaneously with osmotic mini-pumps, infusing either saline or CL (1 mg/kg body weight/day) for 4 weeks. There was no effect of CL on food intake. However, the resting metabolic rate in lean and obese rats increased by 55% and 96% per rat, respectively. Total RWAT weight decreased in both lean and obese rats under influence of CL treatment by 65% and 38%, respectively. Total body weight and body fat were lower in CL treated rats. Detection of uncoupling protein 1 (UCP1) in RWAT was confirmed qualitatively by both immunohistochemistry and immunofluorescence using a rabbit anti rat UCP1 antibody which showed the appearance of a marked increase of this protein in the adipose tissue. Stained semi-thin sections (0.5 μm) also demonstrated abundant nuclei in multilocular adipocytes, in endothelial cells associated with the vasculature, and in interstitial cells. In CL-treated obese rats, a clustering of several multilocular cells around the periphery of a white adipocyte was seen. These results indicate that treatment of both lean and obese Zucker rats with CL induces extensive remodeling of RWAT that includes shrinkage of white adipose tissue, appearance of abundant multilocular cells in RWAT together with the appearance of a marked increase of UCP, preferentially in lean rats.

  6. Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

    PubMed Central

    2013-01-01

    Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing. PMID:23687558

  7. [Economic evaluation of Thrombopoietin Receptor Agonists in the treatment of chronic primary immune thrombocytopenia].

    PubMed

    Parrondo, J; Grande, C; Ibáñez, J; Palau, J; Páramo, J A; Villa, G

    2013-01-01

    Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.

  8. Adverse Effects of GLP-1 Receptor Agonists

    PubMed Central

    Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1

  9. We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders.

    PubMed

    Cheng, Jianjun; Kozikowski, Alan P

    2015-12-01

    The serotonin 2C (5-HT2C ) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C agonists make them preferred candidates for further studies.

  10. We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders

    PubMed Central

    Cheng, Jianjun; Kozikowski, Alan P.

    2016-01-01

    The serotonin 2C (5-HT2C) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C agonists make them preferred candidates for further studies. PMID:26507582

  11. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

    PubMed Central

    Iepsen, E W; Lundgren, J; Dirksen, C; Jensen, J-EB; Pedersen, O; Hansen, T; Madsbad, S; Holst, J J; Torekov, S S

    2015-01-01

    Background: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. Methods: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. Results: Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml−1 (−3.0 (95% confidence interval (CI)=−0.5 to −5.5)), P<0.001 and free leptin index decrease was 43% smaller; −62±15 vs −109±20 (−47 (95% CI=−11 to −83)), P<0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI=−0.6 to −4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=−0.6 to −1)), P<0.001. Fasting glucose was decreased by an additional −0.2±0.1 mmol l−1 in the GLP-1RA group in contrast to the control group, where glucose increased 0.3±0.1 mmol l−1 to the level before weight loss (−0.5mmol l−1 (95% CI=−0.1 to −0.9)), P<0.005. Meal response of peptide

  12. GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women.

    PubMed

    Iepsen, Eva W; Lundgren, Julie R; Hartmann, Bolette; Pedersen, Oluf; Hansen, Torben; Jørgensen, Niklas R; Jensen, Jens-Erik B; Holst, Jens J; Madsbad, Sten; Torekov, Signe S

    2015-08-01

    Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. Randomized control study. Outpatient research hospital clinic. Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 μg/L) vs a 2% (-1 ± 4 μg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.

  13. GABA receptor agonists: pharmacological spectrum and therapeutic actions.

    PubMed

    Bartholini, G

    1985-01-01

    From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by

  14. Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development.

    PubMed

    Li, Zheng; Qiu, Qianqian; Geng, Xinqian; Yang, Jianyong; Huang, Wenlong; Qian, Hai

    2016-08-01

    The alarming prevalence of type 2 diabetes mellitus (T2DM) stimulated the exploitation of new antidiabetic drugs with extended durability and enhanced safety. In this regard, the free fatty acid receptor 1 (FFA1) and FFA4 have emerged as attractive targets in the last decade. FFA1 has prominent advantages in promoting insulin and incretin secretion while FFA4 shows great potential in incretin secretion, insulin sensitization and anti-inflammatory effects. Herein, the authors focus specifically on FFA1 and FFA4 agonists in clinical trials and preclinical development. LY2922470, P11187 and SHR0534 are currently active in clinical trials while the CNX-011-67, SAR1, DS-1558 and BMS-986118 are in preclinical phase. The information for this review is retrieved from Integrity, Scifinder, Espacenet and clinicaltrials.gov databases. Current proof-of-concept in clinical trials suggests that FFA1 agonists have a significant improvement for T2DM without the risk of hypoglycemia. However, there are still several challenging problems including the mechanism of the receptor and the efficacy and safety of the ligands.

  15. In ovo treatment with an estrogen receptor alpha selective agonist causes precocious development of the female reproductive tract of the American alligator (Alligator mississippiensis).

    PubMed

    Doheny, Brenna M; Kohno, Satomi; Parrott, Benjamin B; Guillette, Louis J

    2016-11-01

    The molecular signaling processes involved the differentiation of the Müllerian duct (MD) into the female reproductive tract, or oviduct, in non-mammalian vertebrates are not well understood. Studies in mammals and birds indicate that steroid hormones play a role in this process, as the embryonic MD has been shown to be vulnerable to exogenous estrogens and progestins and environmental endocrine disrupting contaminants. In a previous study, developmental treatment with an estrogen receptor α (ERα) agonist, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), induced significant enlargement of the MD in alligator embryos incubated at a male-producing temperature, which was not observed in embryos treated with an estrogen receptor β (ERβ) agonist, 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY 200070), or with 17β-estradiol (E2). In order to understand the role of estrogen signaling in female alligator oviduct development, we incubated eggs at a female-producing temperature and treated them with E2 and these ER selective agonists, PPT and WAY 200070, just prior to the thermosensitive window of sex determination. At stage 27, one stage prior to hatching, PPT induced significant enlargement of the MD with precocious development of secretory glands and connective tissue differentiation similar to characteristics of mature adult oviduct. PPT treatment in ovo increased mRNA expression of ERβ, progesterone receptor, androgen receptor and insulin-like growth factor 1 in MD at stage 27, while expression of ERα was decreased. Neither WAY 200070 nor E2 treatment induced these effects seen in PPT-treated MD. The results of this study provide insight into the critical factors for healthy reproductive system formation in this sentinel species, although further investigation is needed to determine whether the observed phenomena are directly due to selective stimulation of ERα or related to some other aspect of PPT treatment. Copyright © 2016 Elsevier Inc

  16. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  17. Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.

    PubMed

    Elias, D; Rapoport, M; Cohen, I R; Shechter, Y

    1988-06-01

    In previous studies we reported that immunization of mice with ungulate insulins induced the development of antiinsulin antibodies, which include an idiotype that appeared to recognize the part of the insulin molecule recognized by the hormone receptor. The antiinsulin antibodies of this idiotype were replaced spontaneously by antiidiotypic antibodies. The antiidiotypic antibodies, which persisted for about 14 d, mimicked insulin and functioned as antibodies to the insulin receptor. They induced down regulation, desensitization and refractoriness of the insulin receptor and disturbances in glucose homeostasis in vivo (Shechter, Y., D. Elias, R. Maron, and I.R. Cohen., 1984; Elias, D., R. Maron, I.R. Cohen, and Y. Shechter. 1984, J. Biol. Chem. 259: 6411-6419). We now report that effects of the antiidiotypic antibodies on the insulin receptor effector system can be modified pharmacologically. Administration of the beta-adrenergic agonist isoproterenol during the period of insulin resistance (days 26-40 after primary immunization), largely restored fat cell responsiveness to insulin, and eliminated the appearance of fasting hyperglycemia. This restoration appeared to be caused by inhibition of both insulin receptor desensitization and refractoriness. In contrast, down regulation of insulin receptors was not reversed by isoproterenol treatment in vivo. The effects of treatment with isoproterenol persisted for 2-4 d after termination of treatment. The beta-antagonist, propranolol and more so, the beta 1a-antagonist metoprolol, specifically blocked the effect of isoproterenol at a molar ratio of 3-10:1. Oral administration of the cAMP phosphodiesterase inhibitor, aminophylline, was also effective in inhibiting the development of desensitization in fat cells. These results indicate that treatment with beta 1-adrenergic agonists in vivo, or other agents that elevate cellular cAMP levels, can inhibit the development of the "postbinding" defects induced by insulin

  18. Gremlin: vexing VEGF receptor agonist.

    PubMed

    Claesson-Welsh, Lena

    2010-11-04

    Gremlins are mischievous creatures in English folklore, believed to be the cause of otherwise unexplainable breakdowns (the word gremlins is derived from the Old English "gremian" or "gremman," "to vex"). Gremlin (or Gremlin-1) is also the designation of a secreted protein that is known to regulate bone formation during development. In this issue of Blood, Mitola et al report the novel role of Gremlin as a VEGFR2 agonist and the function of the Gremlin protein seems vexing indeed.

  19. Muscimol as an ionotropic GABA receptor agonist.

    PubMed

    Johnston, Graham A R

    2014-10-01

    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.

  20. 5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity.

    PubMed

    Pierson, Pascale David; Fettes, Alec; Freichel, Christian; Gatti-McArthur, Silvia; Hertel, Cornelia; Huwyler, Jörg; Mohr, Peter; Nakagawa, Toshito; Nettekoven, Matthias; Plancher, Jean-Marc; Raab, Susanne; Richter, Hans; Roche, Olivier; Rodríguez Sarmiento, Rosa María; Schmitt, Monique; Schuler, Franz; Takahashi, Tadakatsu; Taylor, Sven; Ullmer, Christoph; Wiegand, Ruby

    2009-07-09

    Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.

  1. Corepressors of agonist-bound nuclear receptors

    SciTech Connect

    Gurevich, Igor; Aneskievich, Brian J.

    2007-09-15

    Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, 'corner') box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

  2. Opioid receptor agonists reduce brain edema in stroke.

    PubMed

    Yang, Li; Wang, Hezhen; Shah, Kaushik; Karamyan, Vardan T; Abbruscato, Thomas J

    2011-04-06

    Cerebral edema is a leading cause of mortality in stroke patients. The purpose of this study was to assess a non-selective opioid receptor agonist, biphalin, in decreasing reducing brain edema formation using both in vitro and in vivo models of stroke. For the in situ model of ischemia, hippocampal slices were exposed to oxygen glucose deprivation (OGD) conditions and we observed that hippocampal water content was increased, compared to normoxia. Treatment with the mu agonist, Tyr-D-Ala', N-CH, -Phe4, Glyol-Enkephalin (DAMGO), delta opioid agonists, D-pen(2), D-phe(5) enkephalin (DPDPE), and kappa agonist, U50 488, all significantly decreased brain slice water gain. Interestingly, the non-selective agonist, biphalin, exhibited a statistically significant (P<0.01) greater effect in decreasing water content in OGD-exposed hippocampal slices, compared with mu, delta, and kappa selective opioid agonists. Moreover, biphalin exhibited anti-edematous effects in a dose responsive manner. The non-selective opioid antagonist, naloxone, returned the water content nearly back to original OGD values for all opioid agonist treatments, supporting that these effects were mediated by an opioid receptor pathway. Furthermore, biphalin significantly decreased edema (53%) and infarct (48%) ratios, and neuronal recovery from stroke, compared with the vehicle-treated groups in a 12h permanent middle cerebral artery occlusion (MCAO) model of focal ischemia. Biphalin also significantly decreased the cell volume increase in primary neuronal cells exposed to OGD condition. These data suggest that opioid receptor activation may provide neuroprotection during stroke and further investigations are needed in the development of novel opioid agonist as efficacious treatments for brain ischemia.

  3. Antidepressant-like Effects of δ Opioid Receptor Agonists in Animal Models

    PubMed Central

    Saitoh, Akiyoshi; Yamada, Mitsuhiko

    2012-01-01

    Recently, δ opioid receptor agonists have been proposed to be attractive targets for the development of novel antidepressants. Several studies revealed that single treatment of δ opioid receptor agonists produce antidepressant-like effects in the forced swimming test, which is one of the most popular animal models for screening antidepressants. In addition, subchronic treatment with δ opioid receptor agonists has been shown to completely attenuate the hyperemotional responses found in olfactory bulbectomized rats. This animal model exhibits hyperemotional behavior that may mimic the anxiety, aggression, and irritability found in depressed patients, suggesting that δ opioid receptor agonists could be effective in the treatment of these symptoms in depression. On the other hand, prototype δ opioid receptor agonists produce convulsive effects, which limit their therapeutic potential and clinical development. In this review, we presented the current knowledge regarding the antidepressant-like effects of δ opioid receptor agonists, which include some recently developed drugs lacking convulsive effects. PMID:23449756

  4. Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus.

    PubMed

    Los, E L; Deen, P M T; Robben, J H

    2010-05-01

    According to the body's need, water is reabsorbed from the pro-urine that is formed by ultrafiltration in the kidney. This process is regulated by the antidiuretic hormone arginine-vasopressin (AVP), which binds to its type 2 receptor (V2R) in the kidney. Mutations in the gene encoding the V2R often lead to the X-linked inheritable form of nephrogenic diabetes insipidus (NDI), a disorder in which patients are unable to concentrate their urine despite the presence of AVP. Many of these mutations are missense mutations that do not interfere with the intrinsic functionality of V2R, but cause its retention in the endoplasmic reticulum (ER), making it unavailable for AVP binding. Because the current treatments for NDI relieve its symptoms to some extent, but do not cure the disorder, cell-permeable antagonists (pharmacological chaperones) have been successfully used to stabilise the mutant receptors and restore their plasma membrane localisation. Recently, cell-permeable agonists also were shown to rescue ER-retained V2R mutants, leading to increased cAMP levels and translocation of aquaporin-2 to the apical membrane. This makes V2R-specific cell-permeable agonists very promising therapeutics for NDI as a result of misfolded V2R receptors.

  5. Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice

    PubMed Central

    Fitz, Nicholas F.; Mounier, Anais; Wolfe, Cody M.; Nam, Kyong Nyon; Reeves, Valerie L.; Kamboh, Hafsa; Koldamova, Radosveta

    2017-01-01

    ATP-binding cassette transporter A1 (ABCA1) controls cholesterol and phospholipid efflux to lipid-poor apolipoprotein E (APOE) and is transcriptionally controlled by Liver X receptors (LXRs) and Retinoic X Receptors (RXRs). In APP transgenic mice, lack of Abca1 increased Aβ deposition and cognitive deficits. Abca1 haplo-deficiency in mice expressing human APOE isoforms, increased level of Aβ oligomers and worsened memory deficits, preferentially in APOE4 mice. In contrast upregulation of Abca1 by LXR/RXR agonists significantly ameliorated pathological phenotype of those mice. The goal of this study was to examine the effect of LXR agonist T0901317 (T0) on the phenotype and brain transcriptome of APP/E3 and APP/E4 Abca1 haplo-deficient (APP/E3/Abca1+/- and APP/E4/Abca1+/-) mice. Our data demonstrate that activated LXRs/RXR ameliorated APOE4-driven pathological phenotype and significantly affected brain transcriptome. We show that in mice expressing either APOE isoform, T0 treatment increased mRNA level of genes known to affect brain APOE lipidation such as Abca1 and Abcg1. In both APP/E3/Abca1+/- and APP/E4/Abca1+/- mice, the application of LXR agonist significantly increased ABCA1 protein level accompanied by an increased APOE lipidation, and was associated with restoration of APOE4 cognitive deficits, reduced levels of Aβ oligomers, but unchanged amyloid load. Finally, using Gene set enrichment analysis we show a significant APOE isoform specific response to LXR agonist treatment: Gene Ontology categories “Microtubule Based Process” and “Synapse Organization” were differentially affected in T0-treated APP/E4/Abca1+/- mice. Altogether, the results are suggesting that treatment of APP/E4/Abca1+/- mice with LXR agonist T0 ameliorates APOE4-induced AD-like pathology and therefore targeting the LXR-ABCA1-APOE regulatory axis could be effective as a potential therapeutic approach in AD patients, carriers of APOEε4. PMID:28241068

  6. Chronic 5-HT4 receptor agonist treatment restores learning and memory deficits in a neuroendocrine mouse model of anxiety/depression.

    PubMed

    Darcet, Flavie; Gardier, Alain M; David, Denis J; Guilloux, Jean-Philippe

    2016-03-11

    Cognitive disturbances are often reported as serious invalidating symptoms in patients suffering from major depression disorders (MDD) and are not fully corrected by classical monoaminergic antidepressant drugs. If the role of 5-HT4 receptor agonists as cognitive enhancers is well established in naïve animals or in animal models of cognitive impairment, their cognitive effects in the context of stress need to be examined. Using a mouse model of anxiety/depression (CORT model), we reported that a chronic 5-HT4 agonist treatment (RS67333, 1.5mg/kg/day) restored chronic corticosterone-induced cognitive deficits, including episodic-like, associative and spatial learning and memory impairments. On the contrary, a chronic monoaminergic antidepressant drug treatment with fluoxetine (18mg/kg/day) only partially restored spatial learning and memory deficits and had no effect in the associative/contextual task. These results suggest differential mechanisms underlying cognitive effects of these drugs. Finally, the present study highlights 5-HT4 receptor stimulation as a promising therapeutic mechanism to alleviate cognitive symptoms related to MDD.

  7. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.

    PubMed

    Ortega, V E

    2014-07-01

    Beta2 (β2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the β2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Physiologic and weight-focused treatment strategies for managing type 2 diabetes mellitus: the metformin, glucagon-like peptide-1 receptor agonist, and insulin (MGI) approach.

    PubMed

    Nadeau, Daniel A

    2013-05-01

    The prevalence of type 2 diabetes mellitus (T2DM) is rising in association with an increase in obesity rates. Current treatment options for patients with T2DM include lifestyle modifications and numerous antidiabetic medications. Despite the availability of effective and well-tolerated treatments, many patients do not achieve recommended glycemic targets. Lack of efficacy is complicated by the wide range of available agents and little specificity in treatment guidelines, thus challenging clinicians to understand the relative benefits and risks of individual options for each patient. In this article, lifestyle intervention strategies and current antidiabetic agents are evaluated for their efficacy, safety, and weight-loss potential. Because of the heterogeneous and progressive nature of T2DM, physicians should advocate approaches that emphasize weight management, limit the risk of hypoglycemia and adverse events, and focus on the core pathophysiologic defects in patients with T2DM. A healthy, plant-based diet that is low in saturated fat and refined carbohydrates but high in whole grains, vegetables, legumes, and fruits, coupled with resistance and aerobic exercise regimens, are recommended for patients with T2DM. When necessary, drug intervention, described in this article as the MGI (metformin, glucagon-like peptide-1 receptor agonist, and insulin) approach, should begin with metformin and progress to the early addition of glucagon-like peptide-1 receptor agonists because of their weight loss potential and ability to target multiple pathophysiologic defects in patients with T2DM. For most patients, treatments that induce weight gain and hypoglycemia should be avoided. Long-acting insulin should be initiated if glycemic control is not achieved with metformin and glucagon-like peptide-1 receptor agonist combination therapy, focusing on long-acting insulin analogs that induce the least weight gain and have the lowest hypoglycemic risk. Ultimately, a patient

  9. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.

  10. Emerging strategies for exploiting cannabinoid receptor agonists as medicines

    PubMed Central

    Pertwee, Roger G

    2009-01-01

    Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; Δ9-tetrahydrocannabinol) and Sativex® (Δ9-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) ‘multi-targeting’. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  11. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.

    PubMed

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel

    2011-02-25

    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  12. Physician perceptions of GLP-1 receptor agonists in the UK.

    PubMed

    Matza, Louis S; Curtis, Sarah E; Jordan, Jessica B; Adetunji, Omolara; Martin, Sherry A; Boye, Kristina S

    2016-05-01

    Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK. Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014. Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians' most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs. Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted

  13. Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease

    PubMed Central

    Farah, Benjamin L.; Madden, Lauran; Li, Songtao; Nance, Sierra; Bird, Andrew; Bursac, Nenad; Yen, Paul M.; Young, Sarah P.; Koeberl, Dwight D.

    2014-01-01

    Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.—Farah, B. L., Madden, L., Li, S., Nance, S., Bird, A., Bursac, N., Yen, P. M., Young, S. P., Koeberl, D. D. Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with

  14. β‐Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake

    PubMed Central

    Chiang, T; Sansuk, K

    2016-01-01

    Background and Purpose δ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co‐morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β‐arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. Experimental Approach We used three diarylmethylpiperazine‐based non‐peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN‐67, KNT127 and NIH11082). We tested these agonists in cAMP and β‐arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β‐arrestin 2 knockout mice and a model of depression‐like behaviour to further study the role of β‐arrestin 2 in δ receptor pharmacology. Key Results All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β‐arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β‐arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression‐like behaviour were β‐arrestin 2‐dependent. Conclusions and Implications Our finding that δ receptor agonists that strongly recruit β‐arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders. © 2015 The British Pharmacological Society PMID:26507558

  15. β-Arrestin 2 dependence of δ opioid receptor agonists is correlated with alcohol intake.

    PubMed

    Chiang, T; Sansuk, K; van Rijn, R M

    2016-01-01

    δ Opioid receptor agonists are being developed as potential treatments for depression and alcohol use disorders. This is particularly interesting as depression is frequently co-morbid with alcohol use disorders. Yet we have previously shown that δ receptor agonists range widely in their ability to modulate alcohol intake; certain δ receptor agonists actually increase alcohol consumption in mice. We propose that variations in β-arrestin 2 recruitment contribute to the differential behavioural profile of δ receptor agonists. We used three diarylmethylpiperazine-based non-peptidic δ receptor selective agonists (SNC80, SNC162 and ARM390) and three structurally diverse δ receptor agonists (TAN-67, KNT127 and NIH11082). We tested these agonists in cAMP and β-arrestin 2 recruitment assays and a behavioural assay of alcohol intake in male C57BL/6 mice. We used β-arrestin 2 knockout mice and a model of depression-like behaviour to further study the role of β-arrestin 2 in δ receptor pharmacology. All six tested δ receptor agonists were full agonists in the cAMP assay but displayed distinct β-arrestin 2 recruitment efficacy. The efficacy of δ receptor agonists to recruit β-arrestin 2 positively correlated with their ability to increase alcohol intake (P < 0.01). The effects of the very efficacious recruiter SNC80 on alcohol intake, alcohol place preference and depression-like behaviour were β-arrestin 2-dependent. Our finding that δ receptor agonists that strongly recruit β-arrestin 2 can increase alcohol intake carries important ramifications for drug development of δ receptor agonists for treatment of alcohol use disorders and depressive disorders. © 2015 The British Pharmacological Society

  16. Chronic treatment with the G protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats.

    PubMed

    Lindsey, Sarah Hoffmann; Cohen, Jonathan A; Brosnihan, K Bridget; Gallagher, Patricia E; Chappell, Mark C

    2009-08-01

    The mRen2.Lewis congenic strain is an estrogen-sensitive model of hypertension whereby estrogen depletion produces a significant and sustained increase in blood pressure. The recent identification of G protein-coupled receptor 30 (GPR30) as a third estrogen receptor isotype prompted us to test the hypothesis that this novel receptor exhibits beneficial cardiovascular actions in the hypertensive female mRen2.Lewis rat. Intact female, ovariectomized female (OVX), and male mRen2.Lewis rats were treated with the selective GPR30 agonist G-1 or vehicle via osmotic minipump for 2 wk. G-1 significantly reduced systolic blood pressure in OVX (178 +/- 7 to 142 +/- 10 mm Hg, P < 0.001, n = 8) but not intact female (144 +/- 3 to 143 +/- 5 mm Hg, P > 0.05, n = 5) or male mRen2.Lewis rats (207 +/- 7 to 192 +/- 5 mm Hg, P > 0.05, n = 7). G-1 did not alter uterine or body weight in OVX, suggesting activation of a receptor distinct from estrogen receptor-alpha and -beta. In isolated aortic rings from OVX, G-1 reduced constriction in response to angiotensin II. Vascular angiotensin-converting enzyme and angiotensin type 1 receptor mRNA were also lower, whereas angiotensin-converting enzyme-2 mRNA was increased. G-1 treatment in OVX was not associated with alterations in either endothelial nitric oxide synthase expression or acetylcholine-induced relaxation. Immunohistochemical staining for GPR30 was evident in both the intima and media of the aorta. We conclude that the novel estrogen receptor GPR30 may contribute to the beneficial cardiovascular actions of estrogen in female mRen2.Lewis rats through regulation of vascular components of the renin-angiotensin system.

  17. Is there a justification for classifying GLP-1 receptor agonists as basal and prandial?

    PubMed

    Miñambres, Inka; Pérez, Antonio

    2017-01-01

    Several GLP-1 receptor agonists are currently available for treatment of type 2 diabetic patients. Based on their pharmacokinetic/pharmacodynamic profile, these drugs are classified as short-acting GLP-1 receptor agonists (exenatide and lixisenatide) or long-acting GLP-1 receptor agonists (exenatide-LAR, liraglutide, albiglutide, and dulaglutide). In clinical practice, they are also classified as basal or prandial GLP-1 receptor agonists to differentiate between patients who would benefit more from one or another based on characteristics such as previous treatment and the predominance of fasting or postprandial hyperglycemia. In the present article we examine available data on the pharmacokinetic characteristics of the various GLP-1 agonists and compare their effects with respect to the main parameters used to evaluate glycemic control. The article also analyzes whether the differences between the different GLP-1 agonists justify their classification as basal or prandial.

  18. Agonists block currents through acetylcholine receptor channels.

    PubMed Central

    Sine, S M; Steinbach, J H

    1984-01-01

    We have examined the effects of high concentrations of cholinergic agonists on currents through single acetylcholine receptor (AChR) channels on clonal BC3H1 cells. We find that raised concentrations of acetylcholine (ACh; above 300 microM) or carbamylcholine (Carb; above 1,000 microM) produce a voltage- and concentration-dependent reduction in the mean single-channel current. Raised concentrations of suberyldicholine (Sub; above 3 microM) produce a voltage- and concentration-dependent increase in the number of brief duration low-conductance interruptions of open-channel currents. These observations can be quantitatively described by a model in which agonist molecules enter and transiently occlude the ion-channel of the AChR. PMID:6478036

  19. Cariprazine for the Treatment of Schizophrenia: A Review of this Dopamine D3-Preferring D3/D2 Receptor Partial Agonist.

    PubMed

    Citrome, Leslie

    2016-01-01

    Cariprazine is an antipsychotic medication and received approval by the U.S. Food and Drug Administration for the treatment of schizophrenia in September 2015. Cariprazine is a dopamine D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors. The recommended dose range of cariprazine for the treatment of schizophrenia is 1.5-6 mg/d; the starting dose of 1.5 mg/d is potentially therapeutic. Cariprazine is administered once daily and is primarily metabolized in the liver through the CYP3A4 enzyme system and, to a lesser extent, by CYP2D6. There are two active metabolites of note, desmethyl-cariprazine and didesmethyl-cariprazine; the latter's half-life is substantially longer than that for cariprazine and systemic exposure to didesmethyl-cariprazine is several times higher than that for cariprazine. Three positive, 6-week, Phase 2/3, randomized controlled trials in acute schizophrenia demonstrated superiority of cariprazine over placebo. Pooled responder rates were 31% for cariprazine 1.5-6 mg/d vs. 21% for placebo, resulting in a number needed to treat (NNT) of 10. In a 26-72 week, randomized withdrawal study, significantly fewer patients relapsed in the cariprazine group compared with placebo (24.8% vs. 47.5%), resulting in an NNT of 5. The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) are extrapyramidal symptoms (number needed to harm [NNH] 15 for cariprazine 1.5-3 mg/d vs. placebo and NNH 10 for 4.5-6 mg/d vs. placebo) and akathisia (NNH 20 for 1.5-3 mg/d vs. placebo and NNH 12 for 4.5-6 mg/d vs. placebo). Short-term weight gain appears small (approximately 8% of patients receiving cariprazine 1.5-6 mg/d gained ≥7% body weight from baseline, compared with 5% for those randomized to placebo, resulting in an NNH of 34). Cariprazine is associated with no clinically

  20. Comparison of the Therapeutic Response to Treatment with a 177Lu-Labeled Somatostatin Receptor Agonist and Antagonist in Preclinical Models.

    PubMed

    Dalm, Simone U; Nonnekens, Julie; Doeswijk, Gabriela N; de Blois, Erik; van Gent, Dik C; Konijnenberg, Mark W; de Jong, Marion

    2016-02-01

    Peptide receptor scintigraphy and peptide receptor radionuclide therapy using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated the superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic antitumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of (177)Lu-DOTA-octreotate, an SSTR agonist, and (177)Lu-DOTA-JR11, an SSTR antagonist. We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double-strand breaks, by determining the number of p53 binding protein 1 foci, after incubating SSTR2-positive cells with (177)Lu-diethylene triamine pentaacetic acid, (177)Lu-DOTA-octreotate, or (177)Lu-DOTA-JR11. Also, biodistribution studies were performed in tumor-xenografted mice to determine the optimal dose for therapy experiments. Afterward, in vivo therapy experiments comparing the effect of (177)Lu-DOTA-octreotate and (177)Lu-DOTA-JR11 were performed in this same animal model. We found a 5-times-higher uptake of (177)Lu-DOTA-JR11 than of (177)Lu-DOTA-octreotate. The major part (88% ± 1%) of the antagonist uptake was membrane-bound, whereas 74% ± 3% of the total receptor agonist uptake was internalized. Cells treated with (177)Lu-DOTA-JR11 showed 2 times more p53-binding protein 1 foci than cells treated with (177)Lu-DOTA-octreotate. Biodistribution studies with (177)Lu-DOTA-JR11 (0.5 μg/30 MBq) resulted in the highest tumor radiation dose of 1.8 ± 0.7 Gy/MBq, 4.4 times higher than the highest tumor radiation dose found for (177)Lu-DOTA-octreotate. In vivo therapy studies

  1. Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner.

    PubMed

    Barrett, Catherine E; Modi, Meera E; Zhang, Billy C; Walum, Hasse; Inoue, Kiyoshi; Young, Larry J

    2014-10-01

    The melanocortin receptor (MCR) system has been studied extensively for its role in feeding and sexual behavior, but effects on social behavior have received little attention. α-MSH interacts with neural systems involved in sociality, including oxytocin, dopamine, and opioid systems. Acute melanotan-II (MTII), an MC3/4R agonist, potentiates brain oxytocin (OT) release and facilitates OT-dependent partner preference formation in socially monogamous prairie voles. Here we examined the long-term impact of early-life MCR stimulation on hypothalamic neuronal activity and social development in prairie voles. Male and female voles were given daily subcutaneous injections of 10 mg/kg MTII or saline between postnatal days (PND) 1-7. Neonatally-treated males displayed a reduction in initiated play fighting bouts as juveniles compared to control males. Neonatal exposure to MTII facilitated partner preference formation in adult females, but not males, after a brief cohabitation with an opposite-sex partner. Acute MTII injection elicited a significant burst of the immediate early gene EGR-1 immunoreactivity in hypothalamic OT, vasopressin, and corticotrophin releasing factor neurons, when tested in PND 6-7 animals. Daily neonatal treatment with 1 mg/kg of a more selective, brain penetrant MC4R agonist, PF44687, promoted adult partner preferences in both females and males compared with vehicle controls. Thus, developmental exposure to MCR agonists lead to a persistent change in social behavior, suggestive of structural or functional changes in the neural circuits involved in the formation of social relationships.

  2. Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.

    PubMed

    Liu, Jianhua; Yu, Li-Fang; Eaton, J Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Lowe, David A; Brunner, Dani; Lukas, Ronald J; Kozikowski, Alan P

    2011-10-27

    Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

  3. Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists.

    PubMed

    Maguire, David R; France, Charles P

    2014-11-01

    Cannabinoid receptor agonists, such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ(9)-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ(9)-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ(9)-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ(9)-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.

  4. Dopamine receptor agonists for protection and repair in Parkinson's disease.

    PubMed

    Ferrari-Toninelli, Giulia; Bonini, Sara A; Cenini, Giovanna; Maccarinelli, Giuseppina; Grilli, Mariagrazia; Uberti, Daniela; Memo, Maurizio

    2008-01-01

    Dopamine agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease. It is generally believed that treatment with these drugs is symptomatic rather than curative and it does not stop or delay the progression of neuronal degeneration. However, several dopamine agonists of the D2-receptor family have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson's disease models. Here we summarize some recent molecular evidences underlining the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson's disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These neuroprotective activities are molecule-specific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role.

  5. Small-molecule AT2 receptor agonists.

    PubMed

    Hallberg, Mathias; Sumners, Colin; Steckelings, U Muscha; Hallberg, Anders

    2017-06-13

    The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (Ki = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented. © 2017 Wiley Periodicals, Inc.

  6. Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

    PubMed

    Yi, Bitna; Jahangir, Alam; Evans, Andrew K; Briggs, Denise; Ravina, Kristine; Ernest, Jacqueline; Farimani, Amir B; Sun, Wenchao; Rajadas, Jayakumar; Green, Michael; Feinberg, Evan N; Pande, Vijay S; Shamloo, Mehrdad

    2017-01-01

    The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

  7. Identification of a Promising Drug Candidate for the Treatment of Type 2 Diabetes Based on a P2Y1 Receptor Agonist

    PubMed Central

    Yelovitch, Shir; Barr, Haim M.; Camden, Jean; Weisman, Gary A; Shai, Ela; Varon, David; Fischer, Bilha

    2015-01-01

    The activation by ettracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y1R subtype, increases insulin secretion. Therefure, we developed analogues of the P2Y1R receptor agonist 2 MeS ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y1R agonist (EC50 = 0.038 μM vs 0.0025 μM for 2 MeS-ADP) showing no activity at P2Y21416Rs. Analogue 3A was stable at pH 1.4 (t½ = 7.3 h) and resistant to hydrolysis vs 2-MeS ADP by alkaline phosphatase (t½ = 6 vs 4.5 h), human e-NPPl (4% vs 16% hydrolysis after 20 min), and hwnan blood serum (30% vs 50% hydrolysis after 24 h). Intravenous administration of 3A in naive rats decreased blood glucose from 155 mg/dL to normal values, ca. 87 mg/dL, unlike glibenclamide, leading to subnormal values (i.e., 63 mg/dL). Similar observations were made for strepto2otocin (STZ) treated and db+/db− mouse models. Furthermore, 3A inhibits platelet aggregation in vitro and elongates bleeding time in mice (iv administration of 30 mg of 3A/kg), increasing bleeding time to 16 vs 9 min for Prasugrel. Oral administration of30 mg/kg 3A to rats increased tail bleeding volwne, similar to aspirin. These findings suggest that 3A may be an effective treatment for type 2 diabetes by reducing both blood glucose levels and platelet aggregation. PMID:22873688

  8. Selective CRF2 receptor agonists ameliorate the anxiety- and depression-like state developed during chronic nicotine treatment and consequent acute withdrawal in mice.

    PubMed

    Bagosi, Zsolt; Palotai, Miklós; Simon, Balázs; Bokor, Péter; Buzás, András; Balangó, Beáta; Pintér, Dávid; Jászberényi, Miklós; Csabafi, Krisztina; Szabó, Gyula

    2016-12-01

    The aim of the present study was to investigate the effects of the selective agonists of the corticotropin-releasing factor (CRF) 2 receptor, urocortin 2 (UCN 2) and urocortin 3 (UCN 3), on the anxiety- and depression-like signs induced by acute nicotine withdrawal in mice. In order to do so, male CFLP mice were exposed for 7 days to repeated intraperitoneal (IP) injection with nicotine or saline solution and 1day of acute withdrawal and then a single intracerebroventricular (ICV) injection with UCN 2, UCN 3 or saline solution. After 30min the mice were observed in an elevated plus-maze test or a forced swim test, for anxiety- and depression-like behavior. After 5min of testing, the plasma corticosterone concentration reflecting the activity of the hypothalamic-pituitary-adrenal (HPA) axis was also determined by a chemo-fluorescent method. Half of the animals were treated ICV and evaluated on the 8th day, the other half on the 9th day. On the 8th day, nicotine-treated mice presented signs of anxiolysis and depression, but no significant elevation of the plasma corticosterone concentration. On the 9th day, nicotine-treated mice exhibited signs of anxiety and depression and a significant increase of the plasma corticosterone levels. Central administration of UCN 2 or UCN 3 ameliorated the anxiety- and depression-like state including the hyperactivity of the HPA axis, developed during acute withdrawal following chronic nicotine treatment. The present study suggests that selective CRF2 receptor agonists could be used as a therapy in nicotine addiction. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression.

    PubMed

    Veselinović, Tanja; Paulzen, Michael; Gründer, Gerhard

    2013-11-01

    Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

  10. Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise.

    PubMed

    Sato, Shogo; Shirato, Ken; Mitsuhashi, Ryosuke; Inoue, Daisuke; Kizaki, Takako; Ohno, Hideki; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

    2013-05-01

    The aim of this study was to clarify the intracellular β2-adrenergic receptor signaling specificity in mouse slow-twitch soleus and fast-twitch tibialis anterior (TA) muscles, resulting from single-dose β2-agonist clenbuterol treatment and acute exercise. At 1, 4, and 24 h after single-dose treatment with clenbuterol or after acute running exercise, the soleus and TA muscles were isolated and subjected to analysis. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased after single-dose clenbuterol treatment and acute exercise in the soleus muscle but not in the TA muscle. Although there was no change in the phosphorylation of Akt after acute exercise in either muscle, phosphorylation of Akt in the soleus muscle increased after single-dose clenbuterol treatment, whereas that in the TA muscle remained unchanged. These results suggest that p38 MAPK and Akt pathways play a functional role in the adaptation to clenbuterol treatment and exercise, particularly in slow-twitch muscles.

  11. Endorphins and food intake: kappa opioid receptor agonists and hyperphagia.

    PubMed

    Cooper, S J; Jackson, A; Kirkham, T C

    1985-11-01

    Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

  12. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  13. GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice.

    PubMed

    Arai, Sawako; Takuma, Kazuhiro; Mizoguchi, Hiroyuki; Ibi, Daisuke; Nagai, Taku; Kamei, Hiroyuki; Kim, Hyoung-Chun; Yamada, Kiyofumi

    2009-01-05

    In this study, we investigated the effects of GABA(A) and GABA(B) receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA(B) receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA(A) receptor agonist, had no significant effect. GABA(B) receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis.

  14. Dopamine receptor 2 activation inhibits ovarian vascular endothelial growth factor secretion in vitro: implications for treatment of ovarian hyperstimulation syndrome with dopamine receptor 2 agonists.

    PubMed

    Ferrero, Hortensia; García-Pascual, Carmen M; Gómez, Raúl; Delgado-Rosas, Francisco; Cauli, Omar; Simón, Carlos; Gaytán, Francisco; Pellicer, Antonio

    2014-05-01

    To ascertain whether vascular endothelial growth factor (VEGF) secretion by luteinized granulosa cells (GCs) is modulated by the dopaminergic system in a dose-dependent fashion and how this is related to the differential efficacy of dopamine receptor 2 (D2)-agonists (D2-ag) in preventing ovarian hyperstimulation syndrome (OHSS). The relationship between the dopaminergic system and VEGF secretion in luteinized GCs was evaluated. Archived human ovaries were immunostained to characterize D2 expression. University affiliated infertility center. Premenopausal women and egg donors. Luteinized GCs were cultured with the D2-ag cabergoline. Human ovarian sections were immunostained for D2. The VEGF was measured by ELISA and D2 expression was evaluated by In-Cell ELISA. The D2 expression throughout the luteal phase was characterized by immunohistochemistry. The VEGF secretion was decreased by the D2-ag in a dose-dependent fashion. The efficiency of this process was correlated with the amount of D2 expressed by luteinized GCs. A decrease in D2 expression in ovarian sections was observed during the late luteal phase. The efficacy of D2-ags in preventing OHSS might rely on their capacity to inhibit VEGF secretion by luteinized GCs. Because this capacity is dose-dependent, increasing the intraovarian concentration of D2-ags should be explored as a means of increasing the efficacy of these drugs in preventing OHSS. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  15. Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice.

    PubMed

    Patel, Kartikkumar Navinchandra; Joharapurkar, Amit Arvind; Patel, Vishal; Kshirsagar, Samadhan Govind; Bahekar, Rajesh; Srivastava, Brijesh Kumar; Jain, Mukul R

    2014-12-01

    Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

  16. Anxiogenic-like action of caerulein, a CCK-8 receptor agonist, in the mouse: influence of acute and subchronic diazepam treatment.

    PubMed

    Harro, J; Põld, M; Vasar, E

    1990-01-01

    Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at non-sedative doses (100 ng/kg-1 micrograms/kg i.p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 receptor. Acute treatment with low doses (0.1-0.75 mg/kg i.p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i.p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i.p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers.

  17. Novel actions of inverse agonists on 5-HT2C receptor systems.

    PubMed

    Berg, K A; Stout, B D; Cropper, J D; Maayani, S; Clarke, W P

    1999-05-01

    In cell systems where ligand-independent receptor activity is optimized (such as when receptors are overexpressed or mutated), acute treatment with inverse agonists reduces basal effector activity whereas prolonged exposure leads to sensitization of receptor systems and receptor up-regulation. Few studies, however, have reported effects of inverse agonists in systems where nonmutated receptors are expressed at relatively low density. Here, we investigated the effects of inverse agonists at human serotonin (5-HT)2C receptors expressed stably in Chinese hamster ovary cells ( approximately 250 fmol/mg protein). In these cells, there is no receptor reserve for 5-HT and 5-HT2C inverse agonists did not reduce basal inositol phosphate (IP) accumulation nor arachidonic acid (AA) release but behaved as simple competitive antagonists, suggesting that these receptors are not overexpressed. Prolonged treatment (24 h) with inverse agonists enhanced selectively 5-HT2C-mediated IP accumulation but not AA release. The enhancing effect occurred within 4 h of treatment, reversed within 3 to 4 h (after 24-h treatment), and could be blocked with neutral antagonists or weak positive agonists. The enhanced responsiveness was not due to receptor up-regulation but may involve changes in the expression of the G protein, Galphaq/11 and possibly Galpha12 and Galpha13. Interestingly, 24-h exposure to inverse agonists acting at 5-HT2C receptors also selectively enhanced IP accumulation, but not AA release, elicited by activation of endogenous purinergic receptors. These data suggest that actions of inverse agonists may be mediated through effects on receptor systems that are not direct targets for these drugs.

  18. Differential opioid agonist regulation of the mouse mu opioid receptor.

    PubMed

    Blake, A D; Bot, G; Freeman, J C; Reisine, T

    1997-01-10

    Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.

  19. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists' treatment: a meta-analysis of randomized controlled trials.

    PubMed

    Su, Bin; Sheng, Hui; Zhang, Manna; Bu, Le; Yang, Peng; Li, Liang; Li, Fei; Sheng, Chunjun; Han, Yuqi; Qu, Shen; Wang, Jiying

    2015-02-01

    Traditional anti-diabetic drugs may have negative or positive effects on risk of bone fractures. Yet the relationship between the new class glucagon-like peptide-1 receptor agonists (GLP-1 RA) and risk of bone fractures has not been established. We performed a meta-analysis including randomized controlled trials (RCT) to study the risk of bone fractures associated with liraglutide or exenatide, compared to placebo or other active drugs. We searched MEDLINE, EMBASE, and clinical trial registration websites for published or unpublished RCTs comparing the effects of liraglutide or exenatide with comparators. Only studies with disclosed bone fracture data were included. Separate pooled analysis was performed for liraglutide or exenatide, respectively, by calculating Mantel-Haenszel odds ratio (MH-OR). 16 RCTs were identified including a total of 11,206 patients. Liraglutide treatment was associated with a significant reduced risk of incident bone fractures (MH-OR=0.38, 95% CI 0.17-0.87); however, exenatide treatment was associated with an elevated risk of incident bone fractures (MH-OR=2.09, 95% CI 1.03-4.21). Publication bias and heterogeneity between studies were not observed. Our study demonstrated a divergent risk of bone fractures associated with different GLP-1 RA treatments. The current findings need to be confirmed by future well-designed prospective or RCT studies.

  20. Randomized clinical trial: effect of the 5-HT4 receptor agonist revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment

    PubMed Central

    Tack, J; Zerbib, F; Blondeau, K; des Varannes, S B; Piessevaux, H; Borovicka, J; Mion, F; Fox, M; Bredenoord, A J; Louis, H; Dedrie, S; Hoppenbrouwers, M; Meulemans, A; Rykx, A; Thielemans, L; Ruth, M

    2015-01-01

    Background Approximately, 20–30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI. Methods This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (http://ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires. Key Results In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed. Conclusions & Inferences No clear differences were seen in reflux parameters between the placebo and revexepride groups. PMID:25530111

  1. Co-administration of delta- and mu-opioid receptor agonists promotes peripheral opioid receptor function

    PubMed Central

    Schramm, Cicely L.; Honda, Christopher N.

    2010-01-01

    Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of μ- and δ-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the μ- and δ-opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naïve rats and on potassium-evoked release of CGRP from sciatic nerves of naïve rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally-restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co-application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another μ-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, δ-opioid receptor agonists enhance the effect of μ-opioid receptor agonists in the periphery, and local co-administration of δ- and μ-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain. PMID:20970925

  2. Cardiovascular effects of melatonin receptor agonists.

    PubMed

    Paulis, Ludovit; Simko, Fedor; Laudon, Moshe

    2012-11-01

    Melatonin synchronizes circadian rhythms with light/dark period and it was demonstrated to correct chronodisruption. Several melatonin receptor agonists with improved pharmacokinetics or increased receptor affinity are being developed, three of them are already in clinical use. However, the actions of melatonin extend beyond chronobiology to cardiovascular and metabolic systems as well. Given the high prevalence of cardiovascular disease and their common occurrence with chronodisruption, it is of utmost importance to classify the cardiometabolic effects of the newly approved and putative melatoninergic drugs. In the present review, the available (although very sparse) data on such effects, in particular by the approved (circadin, ramelteon, agomelatine) or clinically advanced (tasimelteon, piromelatine = Neu-P11, TIK-301) compounds are summarized. The authors have searched for an association with blood pressure, vascular reactivity, ischemia, myocardial and vascular remodeling and metabolic syndrome. The data suggest that cardiovascular effects of melatonin are at least partly mediated via MT(1)/MT(2) receptors and associated with its chronobiotic action. Therefore, despite the sparse direct evidence, it is believed that these effects will be shared by melatonin analogs as well. With the expected approval of novel melatoninergic compounds, it is suggested that the investigation of their cardiovascular effects should no longer be neglected.

  3. Investigation of the mechanism of agonist and inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-05-01

    This study investigated, for the D2 dopamine receptor, the relation between the ability of agonists and inverse agonists to stabilise different states of the receptor and their relative efficacies. Ki values for agonists were determined in competition versus the binding of the antagonist [3H]spiperone. Competition data were fitted best by a two-binding site model (with the exception of bromocriptine, for which a one-binding site model provided the best fit) and agonist affinities for the higher (Kh) (G protein-coupled) and lower affinity (Kl) (G protein-uncoupled) sites determined. Ki values for agonists were also determined in competition versus the binding of the agonist [3H]N-propylnorapomorphine (NPA) to provide a second estimate of Kh. Maximal agonist effects (Emax) and their potencies (EC50) were determined from concentration-response curves for agonist stimulation of guanosine-5'-O-(3-[32S]thiotriphosphate) ([35S]GTPgammaS) binding. The ability of agonists to stabilise the G protein-coupled state of the receptor (Kl/Kh determined from ligand-binding assays) did not correlate with either of two measures of relative efficacy (relative Emax, Kl/EC50) of agonists determined in [35S]GTPgammaS-binding assays, when the data for all of the compounds tested were analysed. For a subset of compounds, however, there was a relation between Kl/Kh and Emax. Competition-binding data versus [3H]spiperone and [3H]NPA for a range of inverse agonists were fitted best by a one-binding site model. Ki values for the inverse agonists tested were slightly lower in competition versus [3H]NPA compared to [3H]spiperone. These data do not provide support for the idea that inverse agonists act by binding preferentially to the ground state of the receptor.

  4. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy

    PubMed Central

    Jakubík, J; Janíčková, H; El-Fakahany, EE; Doležal, V

    2011-01-01

    BACKGROUND AND PURPOSE Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5′-γ−thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [35S]GTPγS and [3H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M2 muscarinic acetylcholine receptor. KEY RESULTS Agonists displayed biphasic competition curves with the antagonist [3H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [3H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from Gi/o G-proteins but only its dissociation from Gs/olf G-proteins. CONCLUSIONS AND IMPLICATIONS These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of Gi/o versus Gs/olf G-proteins that are not identified by conventional GTPγS binding. PMID:20958290

  5. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy.

    PubMed

    Jakubík, J; Janíčková, H; El-Fakahany, E E; Doležal, V

    2011-03-01

    Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5'-γ-thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M₂ muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [³⁵S]GTPγS and [³H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M₂ muscarinic acetylcholine receptor. Agonists displayed biphasic competition curves with the antagonist [³H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [³H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPγS binding. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  6. Alpha-7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress, and brain injury in mice with ischemic stroke and bone fracture.

    PubMed

    Han, Zhenying; Li, Li; Wang, Liang; Degos, Vincent; Maze, Mervyn; Su, Hua

    2014-11-01

    Bone fracture at the acute stage of stroke exacerbates stroke injury by increasing neuroinflammation. We hypothesize that activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) attenuates neuroinflammation and oxidative stress, and reduces brain injury in mice with bone fracture and stroke. Permanent middle cerebral artery occlusion (pMCAO) was performed in C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0.8 mg/kg PHA 568487 (PHA, α-7 nAchR-specific agonist), 6 mg/kg methyllycaconitine (α-7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Behavior was tested 3 days after pMCAO. Neuronal injury, CD68(+) , M1 (pro-inflammatory) and M2 (anti-inflammatory) microglia/macrophages, phosphorylated p65 component of nuclear factor kappa b in microglia/macrophages, oxidative and anti-oxidant gene expression were quantified. Compared to saline-treated mice, PHA-treated mice performed better in behavioral tests, had fewer apoptotic neurons (NeuN(+) TUNEL(+) ), fewer CD68(+) and M1 macrophages, and more M2 macrophages. PHA increased anti-oxidant gene expression and decreased oxidative stress and phosphorylation of nuclear factor kappa b p65. Methyllycaconitine had the opposite effects. Our data indicate that α-7 nAchR agonist treatment reduces neuroinflammation and oxidative stress, which are associated with reduced brain injury in mice with ischemic stroke plus tibia fracture. Bone fracture at the acute stage of stroke exacerbates neuroinflammation, oxidative stress, and brain injury, and our study has shown that the α-7 nAchR agonist, PHA (PHA 568487), attenuates neuroinflammation, oxidative stress, and brain injury in mice with stroke and bone fracture. Hence, PHA could provide an opportunity to develop a new strategy to reduce brain injury in patients suffering from stroke and bone fracture. © 2014 International Society for Neurochemistry.

  7. Agonist-directed desensitization of the β2-adrenergic receptor.

    PubMed

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M; Wu, Qi; Fang, Ye

    2011-04-26

    The β(2)-adrenergic receptor (β(2)AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β(2)AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β(2)AR desensitization at the whole cell level.

  8. Agonist-Directed Desensitization of the β2-Adrenergic Receptor

    PubMed Central

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

    2011-01-01

    The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

  9. Discovery of G Protein-Biased EP2 Receptor Agonists

    PubMed Central

    2016-01-01

    To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. PMID:26985320

  10. Role of nicotine receptor partial agonists in tobacco cessation

    PubMed Central

    Maity, Nivedita; Chand, Prabhat; Murthy, Pratima

    2014-01-01

    One in three adults in India uses tobacco, a highly addictive substance in one or other form. In addition to prevention of tobacco use, offering evidence-based cessation services to dependent tobacco users constitutes an important approach in addressing this serious public health problem. A combination of behavioral methods and pharmacotherapy has shown the most optimal results in tobacco dependence treatment. Among currently available pharmacological agents, drugs that preferentially act on the α4 β2-nicotinic acetyl choline receptor like varenicline and cytisine appear to have relatively better cessation outcomes. These drugs are in general well tolerated and have minimal drug interactions. The odds of quitting tobacco use are at the very least doubled with the use of partial agonists compared with placebo and the outcomes are also superior when compared to nicotine replacement therapy and bupropion. The poor availability of partial agonists and specifically the cost of varenicline, as well as the lack of safety data for cytisine has limited their use world over, particularly in developing countries. Evidence for the benefit of partial agonists is more robust for smoking rather than smokeless forms of tobacco. Although more studies are needed to demonstrate their effectiveness in different populations of tobacco users, present literature supports the use of partial agonists in addition to behavioral methods for optimal outcome in tobacco dependence. PMID:24574554

  11. Quantifying agonist activity at G protein-coupled receptors.

    PubMed

    Ehlert, Frederick J; Suga, Hinako; Griffin, Michael T

    2011-12-26

    When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors. Receptors behave as quantal switches that alternate between active and inactive states (Figure 1). The active state interacts with specific G proteins or other signaling partners. In the absence of ligands, the inactive state predominates. The binding of agonist increases the probability that the receptor will switch into the active state because its affinity constant for the active state (K(b)) is much greater than that for the inactive state (K(a)). The summation of the random outputs of all of the receptors in the population yields a constant level of receptor activation in time. The reciprocal of the concentration of agonist eliciting half-maximal receptor activation is equivalent to the observed affinity constant (K(obs)), and the fraction of agonist-receptor complexes in the active state is defined as efficacy (ε) (Figure 2). Methods for analyzing the downstream responses of GPCRs have been developed that enable the estimation of the K(obs) and relative efficacy of an agonist. In this report, we show how to modify this analysis to estimate the agonist K(b) value relative to that of another agonist. For assays that exhibit constitutive activity, we show how to estimate K(b) in absolute units of M(-1). Our method of analyzing agonist concentration-response curves consists of global nonlinear regression using the operational model. We describe a procedure using the software application, Prism (GraphPad Software, Inc., San Diego, CA). The analysis yields an estimate of the product of K(obs) and a parameter proportional to efficacy (

  12. GLP-1 receptor agonist-induced polyarthritis: a case report.

    PubMed

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo

    2014-08-01

    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  13. Agonists at the δ-opioid receptor modify the binding of µ-receptor agonists to the µ–δ receptor hetero-oligomer

    PubMed Central

    Kabli, N; Martin, N; Fan, T; Nguyen, T; Hasbi, A; Balboni, G; O'Dowd, BF; George, SR

    2010-01-01

    BACKGROUND AND PURPOSE µ- and δ-opioid receptors form heteromeric complexes with unique ligand binding and G protein-coupling profiles linked to G protein α z-subunit (Gαz) activation. However, the mechanism of action of agonists and their regulation of the µ–δ receptor heteromer are not well understood. EXPERIMENTAL APPROACH Competition radioligand binding, cell surface receptor internalization in intact cells, confocal microscopy and receptor immunofluorescence techniques were employed to study the regulation of the µ–δ receptor heteromer in heterologous cells with and without agonist exposure. KEY RESULTS Gαz enhanced affinity of some agonists at µ–δ receptor heteromers, independent of agonist chemical structure. δ-Opioid agonists displaced µ-agonist binding with high affinity from µ–δ heteromers, but not µ receptor homomers, suggestive of δ-agonists occupying a novel µ-receptor ligand binding pocket within the heteromers. Also, δ-agonists induced internalization of µ-opioid receptors in cells co-expressing µ- and δ-receptors, but not those expressing µ-receptors alone, indicative of µ–δ heteromer internalization. This dose-dependent, Pertussis toxin-resistant and clathrin- and dynamin-dependent effect required agonist occupancy of both µ- and δ-opioid receptors. In contrast to µ-receptor homomers, agonist-induced internalization of µ–δ heteromers persisted following chronic morphine exposure. CONCLUSIONS AND IMPLICATIONS The µ–δ receptor heteromer may contain a novel δ-agonist-detected, high-affinity, µ-receptor ligand binding pocket and is regulated differently from the µ-receptor homomer following chronic morphine exposure. Occupancy of both µ- and δ-receptor binding pockets is required for δ-agonist-induced endocytosis of µ–δ receptor heteromers. δ-Opioid agonists target µ–δ receptor heteromers, and thus have a broader pharmacological specificity than previously identified. PMID:20977461

  14. The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

    PubMed Central

    Israel, Heike; Neeb, Lars

    2015-01-01

    More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50–400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient. PMID:25584073

  15. A Double-Chambered Protein Nanocage Loaded with Thrombin Receptor Agonist Peptide (TRAP) and γ-Carboxyglutamic Acid of Protein C (PC-Gla) for Sepsis Treatment.

    PubMed

    Lee, Wonhwa; Seo, Junyoung; Kwak, Soyoung; Park, Eun Ji; Na, Dong Hee; Kim, Soyoun; Lee, You Mie; Kim, In-San; Bae, Jong-Sup

    2015-11-01

    New protein nanocages are designed bearing two functional proteins, γ-carboxyglutamic acid of protein C (PC-Gla) and thrombin receptor agonist peptide (TRAP), and have an anti-septic response. These nanoparticles reduce sepsis-induced organ injury and septic mortality in vivo. Noting that there are currently no medications for severe sepsis, these results show that novel nanoparticles can be used to treat sepsis. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Protein alterations induced by long-term agonist treatment of HEK293 cells expressing thyrotropin-releasing hormone receptor and G11alpha protein.

    PubMed

    Drastichova, Zdenka; Bourova, Lenka; Hejnova, Lucie; Jedelsky, Petr; Svoboda, Petr; Novotny, Jiri

    2010-01-01

    This study aimed to determine whether sustained stimulation with thyrotropin-releasing hormone (TRH), a peptide with important physiological functions, can possibly affect expression of plasma membrane proteins in HEK293 cells expressing high levels of TRH receptor and G(11)alpha protein. Our previous experiments using silver-stained two-dimensional polyacrylamide gel electrophoretograms did not reveal any significant changes in an overall composition of membrane microdomain proteins after long-term treatment with TRH of these cells (Matousek et al. 2005 Cell Biochem Biophys 42: 21-40). Here we used a purified plasma membrane fraction prepared by Percoll gradient centrifugation and proteins resolved by 2D electrophoresis were stained with SYPRO Ruby gel stain. The high enrichment in plasma membrane proteins of this preparation was confirmed by a multifold increase in the number of TRH receptors and agonist stimulated G-protein activity, compared to postnuclear supernatant. By a combination of these approaches we were able to determine a number of clearly discernible protein changes in the plasma membrane-enriched fraction isolated from cells treated with TRH (1 x 10(-5) M, 16 h): 4 proteins disappeared, the level of 18 proteins decreased and the level of 39 proteins increased. Our concomitant immunochemical determinations also indicated a clear down-regulation of G(q/11)alpha proteins in preparations from hormone-treated cells. In parallel, we observed decrease in caspase 3 and alterations in some other apoptotic marker proteins, which were in line with the presumed antiapoptotic effect of TRH.

  17. Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.

    PubMed

    Farah, Benjamin L; Madden, Lauran; Li, Songtao; Nance, Sierra; Bird, Andrew; Bursac, Nenad; Yen, Paul M; Young, Sarah P; Koeberl, Dwight D

    2014-05-01

    Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.

  18. Long-term Cost-effectiveness of Two GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus in the Italian Setting: Liraglutide Versus Lixisenatide.

    PubMed

    Hunt, Barnaby; Kragh, Nana; McConnachie, Ceilidh C; Valentine, William J; Rossi, Maria C; Montagnoli, Roberta

    2017-07-01

    Maintaining glycemic control is the key treatment target for patients with type 2 diabetes mellitus. In addition, the glucagon-like peptide-1 (GLP-1) receptor agonists may be associated with other favorable treatment characteristics, such as reduction in body weight and reduced risk of hypoglycemia compared with traditional diabetes interventions. The aim of the present analysis was to compare the long-term cost-effectiveness of 2 GLP-1 receptor agonists, liraglutide 1.8 mg and lixisenatide 20 μg (both administered once daily), in the treatment of patients with type 2 diabetes failing to achieve glycemic control with metformin monotherapy in the Italian setting. The IMS CORE Diabetes Model was used to project long-term clinical outcomes and subsequent costs (in 2015 Euros [€]) associated with liraglutide 1.8 mg versus lixisenatide 20 μg treatment in a cohort with baseline characteristics derived from the open-label LIRA-LIXI trial (Efficacy and Safety of Liraglutide Versus Lixisenatide as Add-on to Metformin in Subjects With Type 2 Diabetes; NCT01973231) over patient lifetimes from the perspective of a health care payer. Efficacy data were taken from the 26-week end points of the same trial, including changes in glycated hemoglobin, body mass index, serum lipid levels, and hypoglycemic event rates. Outcomes projected included life expectancy, quality-adjusted life expectancy, cumulative incidence and time to onset of diabetes-related complications, and direct medical costs. Outcomes were discounted at 3% annually, and sensitivity analyses were performed. Liraglutide 1.8 mg was associated with improved discounted life expectancy (14.07 vs 13.96 years) and quality-adjusted life expectancy (9.18 vs 9.06 quality-adjusted life years [QALYs]) compared with lixisenatide 20 μg. These improvements were mostly attributable to a greater reduction in glycated hemoglobin level with liraglutide 1.8 mg versus lixisenatide 20 μg, leading to reduced incidence and

  19. Triterpenes from Alisma orientalis act as androgen receptor agonists, progesterone receptor antagonists, and glucocorticoid receptor antagonists.

    PubMed

    Lin, Hsiang-Ru

    2014-08-01

    Alisma orientalis, a well-known traditional medicine, exerts numerous pharmacological effects including anti-diabetes, anti-hepatitis, and anti-diuretics but its bioactivity is not fully clear. Androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) are three members of nuclear receptor superfamily that has been widely targeted for developing treatments for essential diseases including prostate cancer and breast cancer. In this study, two triterpenes, alisol M 23-acetate and alisol A 23-acetate from Alisma orientalis were determined whether they may act as androgen receptor (AR), progesterone receptor (PR), or glucocorticoid receptor (GR) modulators. Indeed, in the transient transfection reporter assays, alisol M 23-acetate and alisol A 23-acetate transactivated AR in dose-dependent manner, while they transrepressed the transactivation effects exerted by agonist-activated PR and GR. Through molecular modeling docking studies, they were shown to respectively interact with AR, PR, or GR ligand binding pocket fairly well. All these results indicate that alisol M 23-acetate and alisol A 23-acetate from Alisma orientalis might possess therapeutic effects through their modulation of AR, PR, and GR pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Treatment intensification in patients with inadequate glycemic control on basal insulin: rationale and clinical evidence for the use of short‐acting and other glucagon‐like peptide‐1 receptor agonists

    PubMed Central

    Bonadonna, Riccardo C.; Gentile, Sandro; Vettor, Roberto; Pozzilli, Paolo

    2016-01-01

    Summary A substantial proportion of patients with type 2 diabetes mellitus do not reach glycemic targets, despite treatment with oral anti‐diabetic drugs and basal insulin therapy. Several options exist for treatment intensification beyond basal insulin, and the treatment paradigm is complex. In this review, the options for treatment intensification will be explored, focusing on drug classes that act via the incretin system and paying particular attention to the short‐acting glucagon‐like peptide‐1 receptor agonists exenatide and lixisenatide. Current treatment guidelines will be summarized and discussed. © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd. PMID:26787264

  1. Octopaminergic agonists for the cockroach neuronal octopamine receptor.

    PubMed

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  2. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  3. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  4. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis.

    PubMed

    Cheng, Huawei; Shang, Yuping; Jiang, Ling; Shi, Tian-lu; Wang, Lin

    2016-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.

  5. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    PubMed

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  6. Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an α7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia

    PubMed Central

    Keefe, Richard SE; Meltzer, Herbert A; Dgetluck, Nancy; Gawryl, Maria; Koenig, Gerhard; Moebius, Hans J; Lombardo, Ilise; Hilt, Dana C

    2015-01-01

    Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.27 or 0.9 mg once daily or placebo for 12 weeks. The primary efficacy end point was the Overall Cognition Index (OCI) score from the CogState computerized battery. Secondary end points include MATRICS Consensus Cognitive Battery (MCCB) (in US patients), the Schizophrenia Cognition Rating Scale (SCoRS) total score, SCoRS global rating, and Positive and Negative Syndrome Scale (PANSS) total and subscale and cognition factor scores. Of 319 randomized patients, 317 were included in the safety population, and 307 were included in the intent-to-treat population. Notable trends in improvement were demonstrated across all cognition scales. For the OCI score, the LS mean difference for encenicline 0.27 mg vs placebo was significant (Cohen's d=0.257; P=0.034). Mean SCoRS total scores decreased showing improvement in function over time, and the difference was significant for encenicline 0.9 mg vs placebo (P=0.011). Furthermore, the difference between encenicline 0.9 mg and placebo was significant for the PANSS Cognition Impairment Domain (P=0.0098, Cohen's d=0.40) and for the PANSS Negative scale (P=0.028, Cohen's d=0.33). Treatment-emergent adverse events were reported at similar frequencies across all treatment groups (39.0% with placebo, 23.4% with encenicline 0.27 mg, and 33.3% with encenicline 0.9 mg). Overall, encenicline was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia. PMID:26089183

  7. Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: A randomised double-blinded placebo-controlled clinical trial.

    PubMed

    Jørgensen, Peter G; Jensen, Magnus T; Mensberg, Pernille; Storgaard, Heidi; Nyby, Signe; Jensen, Jan S; Knop, Filip K; Vilsbøll, Tina

    2017-02-11

    In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP-1RA liraglutide or placebo combined with supervised exercise in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (-7.1 ± 1.6 cm/s (mean ± standard deviation) to -7.7 ± 1.8 cm/s, p = 0.01), but not in the liraglutide group (-7.1 ± 1.4 to -7.0 ± 1.4 cm/s, p = 0.60; between groups: p = 0.02). Similarly, the ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, p = 0.003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, p = 0.87; between groups: p = 0.03). We found no significant differences in heart rate, left ventricular structure or function within or between the groups. In conclusion, addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on left ventricular diastolic function.

  8. Randomized, Double-Blind, Placebo-Controlled Study of Encenicline, an α7 Nicotinic Acetylcholine Receptor Agonist, as a Treatment for Cognitive Impairment in Schizophrenia.

    PubMed

    Keefe, Richard S E; Meltzer, Herbert A; Dgetluck, Nancy; Gawryl, Maria; Koenig, Gerhard; Moebius, Hans J; Lombardo, Ilise; Hilt, Dana C

    2015-12-01

    Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.27 or 0.9 mg once daily or placebo for 12 weeks. The primary efficacy end point was the Overall Cognition Index (OCI) score from the CogState computerized battery. Secondary end points include MATRICS Consensus Cognitive Battery (MCCB) (in US patients), the Schizophrenia Cognition Rating Scale (SCoRS) total score, SCoRS global rating, and Positive and Negative Syndrome Scale (PANSS) total and subscale and cognition factor scores. Of 319 randomized patients, 317 were included in the safety population, and 307 were included in the intent-to-treat population. Notable trends in improvement were demonstrated across all cognition scales. For the OCI score, the LS mean difference for encenicline 0.27 mg vs placebo was significant (Cohen's d=0.257; P=0.034). Mean SCoRS total scores decreased showing improvement in function over time, and the difference was significant for encenicline 0.9 mg vs placebo (P=0.011). Furthermore, the difference between encenicline 0.9 mg and placebo was significant for the PANSS Cognition Impairment Domain (P=0.0098, Cohen's d=0.40) and for the PANSS Negative scale (P=0.028, Cohen's d=0.33). Treatment-emergent adverse events were reported at similar frequencies across all treatment groups (39.0% with placebo, 23.4% with encenicline 0.27 mg, and 33.3% with encenicline 0.9 mg). Overall, encenicline was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia.

  9. Serotonergic agonists behave as partial agonists at the dopamine D2 receptor.

    PubMed

    Rinken, A; Ferré, S; Terasmaa, A; Owman, C; Fuxe, K

    1999-02-25

    RAT dopamine D2short receptors expressed in CHO cells were characterized by activation of [35S]GTPgammaS binding. There were no significant differences between the maximal effects seen in activation of [35S]GTPgammaS binding caused by dopaminergic agonists, but the effects of 5-HT, 8OH-DPAT and 5-methoxytryptamine amounted to 47 +/- 7%, 43 +/- 5% and 70 +/- 7% of the dopamine effect, respectively. The dopaminergic antagonist (+)butaclamol inhibited activations of both types of ligands with equal potency (pA2 = 8.9 +/- 0.1), indicating that only one type of receptor is involved. In competition with [3H]raclopride binding, dopaminergic agonists showed 53 +/- 2% of the binding sites in the GTP-dependent high-affinity state, whereas 5-HT showed only 20 +/- 3%. Taken together, the results indicate that serotonergic agonists behave as typical partial agonists for D2 receptors with potential antiparkinsonian activity.

  10. Pregnane X receptor agonists impair postprandial glucose tolerance.

    PubMed

    Rysä, J; Buler, M; Savolainen, M J; Ruskoaho, H; Hakkola, J; Hukkanen, J

    2013-06-01

    We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.

  11. Traumatic Brain Injury-Induced Cognitive and Histological Deficits Are Attenuated by Delayed and Chronic Treatment with the 5-HT1A-Receptor Agonist Buspirone

    PubMed Central

    Olsen, Adam S.; Sozda, Christopher N.; Cheng, Jeffrey P.; Hoffman, Ann N.

    2012-01-01

    Abstract The aim of this study was to evaluate the potential efficacy of the serotonin1A (5-HT1A) receptor agonist buspirone (BUS) on behavioral and histological outcome after traumatic brain injury (TBI). Ninety-six isoflurane-anesthetized adult male rats were randomized to receive either a controlled cortical impact or sham injury, and then assigned to six TBI and six sham groups receiving one of five doses of BUS (0.01, 0.05, 0.1, 0.3, or 0.5 mg/kg) or saline vehicle (VEH, 1.0 mL/kg). Treatments began 24 h after surgery and were administered intraperitoneally once daily for 3 weeks. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative days 1–5 and 14–19, respectively. Morphologically intact CA1/CA3 cells and cortical lesion volume were quantified at 3 weeks. No differences were observed among the BUS and VEH sham groups in any end-point measure and thus the data were pooled. Regarding the TBI groups, repeated-measures ANOVAs revealed that the 0.3 mg/kg dose of BUS enhanced cognitive performance relative to VEH and the other BUS doses (p<0.05), but did not significantly impact motor function. Moreover, the same dose conferred selective histological protection as evidenced by smaller cortical lesions, but not greater CA1/CA3 cell survival. No significant behavioral or histological differences were observed among the other BUS doses versus VEH. These data indicate that BUS has a narrow therapeutic dose response, and that 0.3 mg/kg is optimal for enhancing spatial learning and memory in this model of TBI. BUS may have potential as a novel pharmacotherapy for clinical TBI. PMID:22416854

  12. [Safety and tolerability of GLP-1 receptor agonists].

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  13. [Safety and tolerability of GLP-1 receptor agonists].

    PubMed

    Soldevila, Berta; Puig-Domingo, Manel

    2014-01-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer.

  14. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.

    PubMed

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ). Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The

  15. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  16. Toll-like receptor agonists in cancer therapy

    PubMed Central

    Adams, Sylvia

    2010-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

  17. Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity.

    PubMed

    Gurevich, V V; Pals-Rylaarsdam, R; Benovic, J L; Hosey, M M; Onorato, J J

    1997-11-14

    The rapid decrease of a response to a persistent stimulus, often termed desensitization, is a widespread biological phenomenon. Signal transduction by numerous G protein-coupled receptors appears to be terminated by a strikingly uniform two-step mechanism, most extensively characterized for the beta2-adrenergic receptor (beta2AR), m2 muscarinic cholinergic receptor (m2 mAChR), and rhodopsin. The model predicts that activated receptor is initially phosphorylated and then tightly binds an arrestin protein that effectively blocks further G protein interaction. Here we report that complexes of beta2AR-arrestin and m2 mAChR-arrestin have a higher affinity for agonists (but not antagonists) than do receptors not complexed with arrestin. The percentage of phosphorylated beta2AR in this high affinity state in the presence of full agonists varied with different arrestins and was enhanced by selective mutations in arrestins. The percentage of high affinity sites also was proportional to the intrinsic activity of an agonist, and the coefficient of proportionality varies for different arrestin proteins. Certain mutant arrestins can form these high affinity complexes with unphosphorylated receptors. Mutations that enhance formation of the agonist-receptor-arrestin complexes should provide useful tools for manipulating both the efficiency of signaling and rate and specificity of receptor internalization.

  18. New Small Molecule Agonists to the Thyrotropin Receptor

    PubMed Central

    Ali, M. Rejwan; Ma, Risheng; David, Martine; Morshed, Syed A.; Ohlmeyer, Michael; Felsenfeld, Dan P.; Lau, Zerlina; Mezei, Mihaly; Davies, Terry F.

    2015-01-01

    Background Novel small molecular ligands (SMLs) to the thyrotropin receptor (TSHR) have potential as improved molecular probes and as therapeutic agents for the treatment of thyroid dysfunction and thyroid cancer. Methods To identify novel SMLs to the TSHR, we developed a transcription-based luciferase-cAMP high-throughput screening system and we screened 48,224 compounds from a 100K library in duplicate. Results We obtained 62 hits using the cut-off criteria of the mean±three standard deviations above the baseline. Twenty molecules with the greatest activity were rescreened against the parent CHO-luciferase cell for nonspecific activation, and we selected two molecules (MS437 and MS438) with the highest potency for further study. These lead molecules demonstrated no detectible cross-reactivity with homologous receptors when tested against luteinizing hormone (LH)/human chorionic gonadotropin receptor and follicle stimulating hormone receptor–expressing cells. Molecule MS437 had a TSHR-stimulating potency with an EC50 of 13×10−8 M, and molecule MS438 had an EC50 of 5.3×10−8 M. The ability of these small molecule agonists to bind to the transmembrane domain of the receptor and initiate signal transduction was suggested by their activation of a chimeric receptor consisting of an LHR ectodomain and a TSHR transmembrane. Molecular modeling demonstrated that these molecules bound to residues S505 and E506 for MS438 and T501 for MS437 in the intrahelical region of transmembrane helix 3. We also examined the G protein activating ability of these molecules using CHO cells co-expressing TSHRs transfected with luciferase reporter vectors in order to measure Gsα, Gβγ, Gαq, and Gα12 activation quantitatively. The MS437 and MS438 molecules showed potent activation of Gsα, Gαq, and Gα12 similar to TSH, but neither the small molecule agonists nor TSH showed activation of the Gβγ pathway. The small molecules MS437 and MS438 also showed upregulation of

  19. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Can the sigma-1 receptor agonist fluvoxamine prevent schizophrenia?

    PubMed

    Hashimoto, Kenji

    2009-12-01

    In the past decade there has been increasing interest in the potential benefit of early pharmacological intervention in schizophrenia. Patients with schizophrenia show nonpsychotic and nonspecific prodromal symptoms (e.g., depression and cognitive deficits) for several years preceding the onset of frank psychosis. Several studies have demonstrated that medication with atypical antipsychotic drugs in people with prodromal symptoms may reduce the risk of subsequent transition to schizophrenia. Furthermore, a naturalistic treatment study in young people with prodromal symptoms demonstrated that medication with antidepressants could prevent the development of psychosis. Although the sample in this study was small, the results were striking. Some antidepressants, including selective serotonin reuptake inhibitors (SSRIs), had high to moderate affinities at the endoplasmic reticulum protein sigma-1 receptors, which are implicated in neuroprotection and neuronal plasticity. Among all antidepressants, fluvoxamine was the most potent sigma-1 receptor agonist. Since the effects of fluroxaming were antagonized by the selective sigma-1 receptor antagonist NE-100. Based on the role of sigma-1 receptors in the pathophysiology of cognition and depression, the author would like to propose a hypothesis that SSRIs (e.g., fluvoxamine) with sigma-1 receptor agonism may reduce the risk of subsequent transition to schizophrenia.

  1. Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches

    USDA-ARS?s Scientific Manuscript database

    Agomelatine (AGM), an analog of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been re...

  2. Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal

    PubMed Central

    Distler, Margaret G.; Plant, Leigh D.; Sokoloff, Greta; Hawk, Andrew J.; Aneas, Ivy; Wuenschell, Gerald E.; Termini, John; Meredith, Stephen C.; Nobrega, Marcelo A.; Palmer, Abraham A.

    2012-01-01

    Glyoxalase 1 (Glo1) expression has previously been associated with anxiety in mice; however, its role in anxiety is controversial, and the underlying mechanism is unknown. Here, we demonstrate that GLO1 increases anxiety by reducing levels of methylglyoxal (MG), a GABAA receptor agonist. Mice overexpressing Glo1 on a Tg bacterial artificial chromosome displayed increased anxiety-like behavior and reduced brain MG concentrations. Treatment with low doses of MG reduced anxiety-like behavior, while higher doses caused locomotor depression, ataxia, and hypothermia, which are characteristic effects of GABAA receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated GABAA receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing GABAA receptor activation. More broadly, our findings potentially link metabolic state, neuronal inhibitory tone, and behavior. Finally, we demonstrated that pharmacological inhibition of GLO1 reduced anxiety, suggesting that GLO1 is a possible target for the treatment of anxiety disorders. PMID:22585572

  3. The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

    PubMed Central

    2012-01-01

    Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans. PMID:23421672

  4. The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability.

    PubMed

    Lin, Ann P; Ko, Mei-Chuan

    2013-02-20

    Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation of NOP and MOP receptors produces synergistic antinociception, it is worth developing bifunctional NOP/MOP ligands. The outcomes of these studies and recent developments provide new perspectives to establish a translational bridge for understanding the biobehavioral functions of NOP receptors in primates and for facilitating the development of NOP-related ligands as a new generation of analgesics without abuse liability in humans.

  5. D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism.

    PubMed

    Hyacinthe, Carole; Barraud, Quentin; Tison, François; Bezard, Erwan; Ghorayeb, Imad

    2014-03-01

    Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders.

  6. Basal Insulin Use With GLP-1 Receptor Agonists.

    PubMed

    Anderson, Sarah L; Trujillo, Jennifer M

    2016-08-01

    IN BRIEF The combination of basal insulin and a glucagon-like peptide 1 receptor agonist is becoming increasingly common and offers several potential benefits to patients with type 2 diabetes. Clinical studies have demonstrated improved glycemic control and low risks of hypoglycemia and weight gain with the combination, which provides a safe and effective alternative to basal-bolus insulin with less treatment burden. Fixed-ratio combination products that administer both agents in a single injection are in the pipeline and will offer additional options for clinicians and patients. This review focuses on the rationale for, clinical evidence on, and implications of using this combination of therapies in the treatment of type 2 diabetes.

  7. Effect of Light and Melatonin and other Melatonin Receptor Agonists on Human Circadian Physiology

    PubMed Central

    Emens, Jonathan S.

    2015-01-01

    Synopsis Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment. PMID:26568121

  8. Effect of Light and Melatonin and Other Melatonin Receptor Agonists on Human Circadian Physiology.

    PubMed

    Emens, Jonathan S; Burgess, Helen J

    2015-12-01

    Circadian (body clock) timing has a profound influence on mental health, physical health, and health behaviors. This review focuses on how light, melatonin, and other melatonin receptor agonist drugs can be used to shift circadian timing in patients with misaligned circadian rhythms. A brief overview of the human circadian system is provided, followed by a discussion of patient characteristics and safety considerations that can influence the treatment of choice. The important features of light treatment, light avoidance, exogenous melatonin, and other melatonin receptor agonists are reviewed, along with some of the practical aspects of light and melatonin treatment.

  9. Combined modality therapy with TRAIL or agonistic death receptor antibodies

    PubMed Central

    Amm, Hope M; Oliver, Patsy G; Lee, Choo Hyung; Li, Yufeng

    2011-01-01

    Molecularly targeted therapies, such as antibodies and small molecule inhibitors have emerged as an important breakthrough in the treatment of many human cancers. One targeted therapy under development is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) due to its ability to induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in most normal cells. TRAIL and apoptosis-inducing agonistic antibodies to the TRAIL death receptors have been the subject of many preclinical and clinical studies in the past decade. However, the sensitivity of individual cancer cell lines of a particular tumor type to these agents varies from highly sensitive to resistant. Various chemotherapy agents have been shown to enhance the apoptosis-inducing capacity of TRAIL receptor-targeted therapies and induce sensitization of TRAIL-resistant cells. This review provides an overview of the mechanisms associated with chemotherapy enhancement of TRAIL receptor-targeted therapies including modulation of the apoptotic (death receptor expression, FLIP and Bcl-2 or inhibitors of apoptosis [IAP] families) as well as cell signaling (NFκB, Akt, p53) pathways. These mechanisms will be important in establishing effective combinations to pursue clinically and in determining relevant targets for future cancer therapies. PMID:21263219

  10. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  11. Toll-Like Receptor 9 Agonists for Cancer Therapy

    PubMed Central

    Melisi, Davide; Frizziero, Melissa; Tamburrino, Anna; Zanotto, Marco; Carbone, Carmine; Piro, Geny; Tortora, Giampaolo

    2014-01-01

    The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required. PMID:28548068

  12. Toll-Like Receptor 9 Agonists for Cancer Therapy.

    PubMed

    Melisi, Davide; Frizziero, Melissa; Tamburrino, Anna; Zanotto, Marco; Carbone, Carmine; Piro, Geny; Tortora, Giampaolo

    2014-08-04

    The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  13. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. © FASEB.

  14. Discovery of Highly Potent Liver X Receptor β Agonists.

    PubMed

    Kick, Ellen K; Busch, Brett B; Martin, Richard; Stevens, William C; Bollu, Venkataiah; Xie, Yinong; Boren, Brant C; Nyman, Michael C; Nanao, Max H; Nguyen, Lam; Plonowski, Artur; Schulman, Ira G; Yan, Grace; Zhang, Huiping; Hou, Xiaoping; Valente, Meriah N; Narayanan, Rangaraj; Behnia, Kamelia; Rodrigues, A David; Brock, Barry; Smalley, James; Cantor, Glenn H; Lupisella, John; Sleph, Paul; Grimm, Denise; Ostrowski, Jacek; Wexler, Ruth R; Kirchgessner, Todd; Mohan, Raju

    2016-12-08

    Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.

  15. Ovariectomy and subsequent treatment with estrogen receptor agonists tune the innate immune system of the hippocampus in middle-aged female rats.

    PubMed

    Sárvári, Miklós; Kalló, Imre; Hrabovszky, Erik; Solymosi, Norbert; Liposits, Zsolt

    2014-01-01

    The innate immune system including microglia has a major contribution to maintenance of the physiological functions of the hippocampus by permanent monitoring of the neural milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to age-related changes ranging from gene expression to network connectivity. The risk of hippocampal deterioration increases with the decline of gonadal hormone supply. To explore the impact of hormone milieu on the function of the innate immune system in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal hormone withdrawal, with or without subsequent estrogen replacement using estradiol and isotype-selective estrogen receptor (ER) agonists. Targeted profiling assessed the status of the innate immune system (macrophage-associated receptors, complement, inhibitory neuronal ligands), local estradiol synthesis (P450 aromatase) and estrogen reception (ER). Results established upregulation of macrophage-associated (Cd45, Iba1, Cd68, Cd11b, Cd18, Fcgr1a, Fcgr2b) and complement (C3, factor B, properdin) genes in response to ovariectomy. Ovariectomy upregulated Cd22 and downregulated semaphorin3A (Sema3a) expression, indicating altered neuronal regulation of microglia. Ovariectomy also led to downregulation of aromatase and upregulation of ERα gene. Of note, analogous changes were observed in the hippocampus of postmenopausal women. In ovariectomized rats, estradiol replacement attenuated Iba1, Cd11b, Fcgr1a, C3, increased mannose receptor Mrc1, Cd163 and reversed Sema3a expression. In contrast, reduced expression of aromatase was not reversed by estradiol. While the effects of ERα agonist closely resembled those of estradiol, ERβ agonist was also capable of attenuating the expression of several macrophage-associated and complement genes. These data together indicate that the innate immune system of the aging hippocampus is highly responsive to the gonadal hormone milieu. In

  16. Agonist-induced phosphorylation and desensitization of the P2Y2 nucleotide receptor.

    PubMed

    Flores, Rosa V; Hernández-Pérez, Melvin G; Aquino, Edna; Garrad, Richard C; Weisman, Gary A; Gonzalez, Fernando A

    2005-12-01

    Purification of HA-tagged P2Y2 receptors from transfected human 1321N1 astrocytoma cells yielded a protein with a molecular size determined by SDS-PAGE to be in the range of 57-76 kDa, which is typical of membrane glycoproteins with heterogeneous complex glycosylation. The protein phosphatase inhibitor, okadaic acid, attenuated the recovery of receptor activity from the agonist-induced desensitized state, suggesting a role for P2Y2 receptor phosphorylation in desensitization. Isolation of HA-tagged P2Y2 nucleotide receptors from metabolically [32P]-labelled cells indicated a (3.8 +/- 0.2)-fold increase in the [32P]-content of the receptor after 15 min of treatment with 100 microM UTP, as compared to immunoprecipitated receptors from untreated control cells. Receptor sequestration studies indicated that approximately 40% of the surface receptors were internalized after a 15-min stimulation with 100 microM UTP. Point mutation of three potential GRK and PKC phosphorylation sites in the third intracellular loop and C-terminal tail of the P2Y2 receptor (namely, S243A, T344A, and S356A) extinguished agonist-induced receptor phosphorylation, caused a marked reduction in the efficacy of UTP to desensitize P2Y2 receptor signalling to intracellular calcium mobilization, and impaired agonist-induced receptor internalization. Activation of PKC isoforms with phorbol 12-myristate 13-acetate that caused heterologous receptor desensitization did not increase the level of P2Y2 receptor phosphorylation. Our results indicate a role for receptor phosphorylation by phorbol-insensitive protein kinases in agonist-induced desensitization of the P2Y2 nucleotide receptor.

  17. Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

    DTIC Science & Technology

    2009-05-01

    found in hot- chili peppers that evokes pain sensation by activating at the TRPV1. TRPV1 and the up-regulation of its expression have been strongly... anti - nociception against capsaicin-induced allodynia in mon- keys (Figure 3). Capsaicin evokes pain sensation by activating at the vanilloid receptor... activation of the NOP receptor produces strong antinociception without abuse liability, and (3) NOP receptor agonists possess a promising therapeutic

  18. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration

    PubMed Central

    Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.

    2014-01-01

    Recent results from laboratory investigations and clinical trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are associated with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clinical benefits of ER agonists for augmenting cognitive function may triumph over the associated side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory molecules with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concentrated on finding the most plausible molecular pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS. PMID:25245209

  19. Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases.

    PubMed

    Niitsu, Tomihisa; Iyo, Masaomi; Hashimoto, Kenji

    2012-01-01

    Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as schizophrenia and psychotic depression. The drugs currently used to treat cognitive impairment have significant limitations, ensuring that the search for more effective therapies remains active. Endoplasmic reticulum protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil and neurosteroids. Among SSRIs, fluvoxamine, a potent sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors. Sigma-1 receptor agonists greatly potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia is significantly improved by sub-chronic administration of sigma-1 receptor agonists such as fluvoxamine, SA4503 (cutamesine) and donepezil. This effect is antagonized by co-administration of NE-100. A positron emission tomography (PET) study using the specific sigma-1 receptor ligand [11C]SA4503 demonstrates that fluvoxamine and donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on sigma-1 receptor agonists as potential therapeutic drugs for the treatment of cognitive impairment in schizophrenia and psychotic depression.

  20. Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.

    PubMed

    Weichert, Dietmar; Stanek, Markus; Hübner, Harald; Gmeiner, Peter

    2016-06-15

    Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Functional receptor coupling to Gi is a mechanism of agonist-promoted desensitization of the beta2-adrenergic receptor.

    PubMed

    Tepe, N M; Liggett, S B

    2000-01-01

    The beta2-adrenergic receptor (beta2AR) couples to Gs activating adenylyl cyclase (AC) and increasing cAMP. Such signaling undergoes desensitization with continued agonist exposure. Beta2AR also couple to Gi after receptor phosphorylation by the cAMP dependent protein kinase A, but the efficiency of such coupling is not known. Given the PKA dependence of beta2AR-Gi coupling, we explored whether this may be a mechanism of agonist-promoted desensitization. HEK293 cells were transfected to express beta2AR or beta2AR and Gialpha2, and then treated with vehicle or the agonist isoproterenol to evoke agonist-promoted beta2AR desensitization. Membrane AC activities showed that Gialpha2 overexpression decreased basal levels, but the fold-stimulation of the AC over basal by agonist was not altered. However, with treatment of the cells with isoproterenol prior to membrane preparation, a marked decrease in agonist-stimulated AC was observed with the cells overexpressing Gialpha2. In the absence of such overexpression, beta2AR desensitization was 23+/-7%, while with 5-fold Gialpha2 overexpression desensitization was 58+/-5% (p<0.01, n=4). The effect of Gi on desensitization was receptor-specific, in that forskolin responses were not altered by G(i)alpha2 overexpression. Thus, acquired beta2AR coupling to Gi is an important mechanism of agonist-promoted desensitization, and pathologic conditions that increase Gi levels contribute to beta2AR dysfunction.

  2. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  3. Agonist and antagonist protect sulfhydrals in the binding site of the D-1 dopamine receptor

    SciTech Connect

    Sidhu, A.; Kebabian, J.W.; Fishman, P.H.

    1986-05-01

    An iodinated compound (/sup 125/I)-SCH 23982 (8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) has been characterized as a specific, high affinity (Kd = 0.7 nM) ligand for the D-1 dopamine receptor. The ligand binding site of the D-1 receptor in rat striatum was inactivated by N-ethylmaleimide (NEM) in a time and concentration dependent manner. The inactivation was rapid and irreversible with a 70% net loss of binding sites. Scatchard analysis of binding to NEM-treated tissue showed a decrease both in receptor number and in radioligand affinity. The remaining receptors retained their selectivity for stereoisomers of both agonist and antagonist. Receptor occupancy by either a D-1 specific agonist or antagonist protected in a dose dependent manner the binding sites from inactivation by NEM; the agonist was more effective than the antagonist. The agonist high affinity site, however, was abolished in the absence or presence of protective compound, presumably because of inactivation of the GTP-binding component of adenylate cyclase. In this regard, there was a total loss of agonist- and forskolin-stimulated adenylate cyclase activity after NEM treatment. The authors conclude that the D-1 dopamine receptor contains NEM-sensitive sulfhydral group(s) at or near the vicinity of the ligand binding site.

  4. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    PubMed Central

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  5. Peroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: preclinical evidence.

    PubMed

    Le Foll, Bernard; Di Ciano, Patricia; Panlilio, Leigh V; Goldberg, Steven R; Ciccocioppo, Roberto

    2013-06-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together these preclinical data indicate that PPAR agonists are promising new medications for drug addiction treatment.

  6. A Novel Method for Screening Adenosine Receptor Specific Agonists for Use in Adenosine Drug Development

    PubMed Central

    Jones, Karlie R.; Choi, Uimook; Gao, Ji-Liang; Thompson, Robert D.; Rodman, Larry E.; Malech, Harry L.; Kang, Elizabeth M.

    2017-01-01

    Agonists that target the A1, A2A, A2B and A3 adenosine receptors have potential to be potent treatment options for a number of diseases, including autoimmune diseases, cardiovascular disease and cancer. Because each of these adenosine receptors plays a distinct role throughout the body, obtaining highly specific receptor agonists is essential. Of these receptors, the adenosine A2AR and A2BR share many sequence and structural similarities but highly differ in their responses to inflammatory stimuli. Our laboratory, using a combination of specially developed cell lines and calcium release analysis hardware, has created a new and faster method for determining specificity of synthetic adenosine agonist compounds for the A2A and A2B receptors in human cells. A2A receptor expression was effectively removed from K562 cells, resulting in the development of a distinct null line. Using HIV-lentivector and plasmid DNA transfection, we also developed A2A and A2B receptor over-expressing lines. As adenosine is known to cause changes in intracellular calcium levels upon addition to cell culture, calcium release can be determined in these cell lines upon compound addition, providing a functional readout of receptor activation and allowing us to isolate the most specific adenosine agonist compounds. PMID:28317879

  7. Virtual screening of CB(2) receptor agonists from bayesian network and high-throughput docking: structural insights into agonist-modulated GPCR features.

    PubMed

    Renault, Nicolas; Laurent, Xavier; Farce, Amaury; El Bakali, Jamal; Mansouri, Roxane; Gervois, Philippe; Millet, Régis; Desreumaux, Pierre; Furman, Christophe; Chavatte, Philippe

    2013-04-01

    The relevance of CB(2)-mediated therapeutics is well established in the treatment of pain, neurodegenerative and gastrointestinal tract disorders. Recent works such as the crystallization of class-A G-protein-coupled receptors in a range of active states and the identification of specific anchoring sites for CB(2) agonists challenged us to design a reliable agonist-bound homology model of CB(2) receptor. Docking-scoring enrichment tests of a high-throughput virtual screening of 140 compounds led to 13 hits within the micromolar affinity range. Most of these hits behaved as CB(2) agonists, among which two novel full agonists emerged. Although the main challenge was a high-throughput docking run targeting an agonist-bound state of a CB(2) model, a prior 2D ligand-based Bayesian network was computed to enrich the input commercial library for 3D screening. The exclusive discovery of agonists illustrates the reliability of this agonist-bound state model for the identification of polar and aromatic amino acids as new agonist-modulated CB(2) features to be integrated in the wide activation pathway of G-protein-coupled receptors.

  8. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.

    PubMed

    Sasmal, Pradip K; Krishna, C Vamsee; Adabala, S Sudheerkumar; Roshaiah, M; Rawoof, Khaji Abdul; Thadi, Emima; Sukumar, K Pavan; Cheera, Srisailam; Abbineni, Chandrasekhar; Rao, K V L Narasimha; Prasanthi, A; Nijhawan, Kamal; Jaleel, Mahaboobi; Iyer, Lakshmi Ramachandran; Chaitanya, T Krishna; Tiwari, Nirbhay Kumar; Krishna, N Lavanya; Potluri, Vijay; Khanna, Ish; Frimurer, Thomas M; Lückmann, Michael; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas

    2015-02-15

    Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks

    NASA Astrophysics Data System (ADS)

    Schäffer, Lauge; Brissette, Renee E.; Spetzler, Jane C.; Pillutla, Renuka C.; Østergaard, Søren; Lennick, Michael; Brandt, Jakob; Fletcher, Paul W.; Danielsen, Gillian M.; Hsiao, Ku-Chuan; Andersen, Asser S.; Dedova, Olga; Ribel, Ulla; Hoeg-Jensen, Thomas; Hertz Hansen, Per; Blume, Arthur J.; Markussen, Jan; Goldstein, Neil I.

    2003-04-01

    Insulin is thought to elicit its effects by crosslinking the two extracellular -subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases.

  10. Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

    DTIC Science & Technology

    2010-05-01

    irritant found in hot- chili peppers that evokes pain sensation by activating at the TRPV1. TRPV1 and the up-regulation of its expression have been 5...Capsaicin is a natural irritant found in hot- chili peppers that evokes pain sensation by activating at the TRPV1. TRPV1 and the up-regulation of its...2) activation of the NOP receptor produces strong antinociception without abuse liability, and (3) NOP receptor agonists possess a promising

  11. Discovery of orally available tetrahydroquinoline-based glucocorticoid receptor agonists.

    PubMed

    Hudson, Andrew R; Higuchi, Robert I; Roach, Steven L; Adams, Mark E; Vassar, Angela; Syka, Peter M; Mais, Dale E; Miner, Jeffrey N; Marschke, Keith B; Zhi, Lin

    2011-03-15

    A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure-activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice

    PubMed Central

    Olson, Katherine E.; Kosloski-Bilek, Lisa M.; Anderson, Kristi M.; Diggs, Breha J.; Clark, Barbara E.; Gledhill, John M.; Shandler, Scott J.; Mosley, R. Lee

    2015-01-01

    Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP's rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration used to model Parkinson's disease (PD). Survival of tyrosine hydroxylase neurons in the substantia nigra was determined by stereological tests after MPTP intoxication in mice pretreated with either VIPR1 or VIPR2 agonist or after adoptive transfer of splenic cell populations from agonist-treated mice administered to MPTP-intoxicated animals. Treatment with VIPR2 agonist or splenocytes from agonist-treated mice resulted in increased neuronal sparing. Immunohistochemical tests showed that agonist-treated mice displayed reductions in microglial responses, with the most pronounced effects in VIPR2 agonist-treated, MPTP-intoxicated mice. In parallel studies, we observed reductions in proinflammatory cytokine release that included IL-17A, IL-6, and IFN-γ and increases in GM-CSF transcripts in CD4+ T cells recovered from VIPR2 agonist-treated animals. Moreover, a phenotypic shift of effector to regulatory T cells was observed. These results support the use of VIPR2-selective agonists as neuroprotective agents for PD treatment. SIGNIFICANCE STATEMENT Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson's disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating

  13. Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.

    PubMed

    Goble, Stephen D; Wang, Liping; Howell, K Lulu; Bansal, Alka; Berger, Richard; Brockunier, Linda; DiSalvo, Jerry; Feighner, Scott; Harper, Bart; He, Jiafang; Hurley, Amanda; Hreniuk, Donna; Parmee, Emma; Robbins, Michael; Salituro, Gino; Sanfiz, Anthony; Streckfuss, Eric; Watkins, Eloisa; Weber, Ann E; Struthers, Mary; Edmondson, Scott D

    2010-03-15

    A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

  14. Retinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis.

    PubMed

    Trasino, S E; Tang, X-H; Jessurun, J; Gudas, L J

    2016-02-01

    To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease. Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). We show that administration of synthetic agonists for RARβ2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle. Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis. © 2015 John Wiley & Sons Ltd.

  15. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice

    PubMed Central

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P.; Wang, Nadan; Tang, Francesca; Knight, Morgan J.; Pan, Shi; Oliver, Brian; Deshpande, Deepak A.

    2017-01-01

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma. PMID:28397820

  16. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.

    PubMed

    Sharma, Pawan; Yi, Roslyn; Nayak, Ajay P; Wang, Nadan; Tang, Francesca; Knight, Morgan J; Pan, Shi; Oliver, Brian; Deshpande, Deepak A

    2017-04-11

    Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

  17. Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors *

    PubMed Central

    Ryman-Rasmussen, Jessica P.; Griffith, Adam; Oloff, Scott; Vaidehi, Nagarajan; Brown, Justin T.; Goddard, William A.; Mailman, Richard B.

    2007-01-01

    Recently, we demonstrated that D1 agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D1 receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D1 receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D1 receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1 h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D1 receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D1 receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D1 receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D1 receptor that are distal from the ligand binding domain. PMID:17067639

  18. Retinoic Acid Receptor β2 Agonists Restore Glycemic Control In Diabetes and Reduce Steatosis

    PubMed Central

    Trasino, Steven E.; Tang, Xiao-Han; Jessurun, Jose; Gudas, Lorraine J.

    2016-01-01

    Aims Retinoids (vitamin A (retinol), and structurally related molecules) possess metabolic modulating properties, prompting new interest in their role in the treatment of diabetes and fatty liver disease, but little is known about the effects of specific retinoic acid receptor (RAR) agonists in these diseases. Materials and Methods Synthetic agonists for retinoic acid receptor RARβ2 were administered to wild type (wt) mice in a model of high fat diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). Results We demonstrate that administration of synthetic agonists for the retinoic acid receptor RARβ2 to either wild type (wt) mice in a model of high fat diet (HFD)-induced type 2 diabetes (T2D) or to ob/ob and db/db mice (genetic models of obesity-associated T2D) reduces hyperglycemia, peripheral insulin resistance, and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation, and oxidative stress in the liver, pancreas, and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as SREBP1 and FASN (fatty acid synthase), and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle. Conclusions Collectively, our data show that orally active, rapidly acting, high affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis. PMID:26462866

  19. The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Walker, Adrian B; Varughese, George I

    2014-03-01

    Rapid improvement in glycaemic control with GLP-1 receptor agonist (RA) therapy has been reported to be associated with significant progression of diabetic retinopathy. This deterioration is transient, and continuing GLP-1 RA treatment is associated with reversal of this phenomenon. Pre-existent maculopathy, higher grade of retinopathy and longer duration of diabetes may be risk factors for persistent deterioration.

  20. Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

    PubMed

    Farzin, Davood; Nosrati, Farnaz

    2007-01-15

    The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.

  1. Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.

    PubMed

    Duarte, E P; Oliveira, C R; Carvalho, A P

    1988-03-01

    The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of

  2. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface

    NASA Astrophysics Data System (ADS)

    Gerszten, Robert E.; Chen, Ji; Ishli, Maki; Ishil, Kenji; Wang, Ling; Nanevicz, Tania; Turck, Christoph W.; Vu, Thien-Khai H.; Coughlin, Shaun R.

    1994-04-01

    G-PROTEIN-COUPLED receptors for catecholamines and some other small ligands are activated when agonists bind to the transmem-brane region of the receptor1. The docking interactions through which peptide agonists activate their receptors are less well characterized2-7. The thrombin receptor is a specialized peptide receptor. It is activated by binding its tethered ligand domain, which is unmasked upon receptor cleavage by thrombin8,9. Human and Xenopus thrombin receptor homologues are each selectively activated by the agonist peptide representing their respective tethered ligand domains. Here we identify receptor domains that confer this agonist specificity by replacing the Xenopus receptor's amino-terminal exodomain and three extracellular loops with the corresponding human structures. This switches receptor specificity from Xenopus to human. The specificity of these thrombin receptors for their respective peptide agonists is thus determined by their extracellular surfaces. Our results indicate that agonist interaction with extracellular domains is important for thrombin receptor activation.

  3. Effect of AVE 0991 angiotensin-(1-7) receptor agonist treatment on elemental and biomolecular content and distribution in atherosclerotic plaques of apoE-knockout mice

    NASA Astrophysics Data System (ADS)

    Kowalska, J.; Gajda, M.; Jawień, J.; Kwiatek, W. M.; Appel, K.; Dumas, P.

    2013-12-01

    Gene-targeted apolipoprotein E-knockout (apoE-KO) mice display early and highly progressive vascular lesions containing lipid deposits and they became a reliable animal model to study atherosclerosis. The aim of the present study was to investigate the effect of AVE 0991 angiotensin-(1-7) receptor agonist on the distribution of selected pro- and anti- inflammatory elements as well as biomolecules in atherosclerotic plaques of apoE-knockout mice. Synchrotron radiation-based X-ray fluorescence (micro-XRF) and Fourier Transform Infrared (micro-FTIR) microspectroscopies were applied. Two-month-old apoE-KO mice were fed for following four months diet supplemented with AVE 0991 (0.58 μmol/kg b.w. per day). Histological sections of ascending aortas were analyzed spectroscopically. The distribution of P, Ca, Fe and Zn were found to correspond with histological structure of the lesion. Significantly lower contents of P, Ca, Zn and significantly higher content of Fe were observed in animals treated with AVE 0991. Biomolecular analysis showed lower lipids saturation level and lower lipid to protein ratio in AVE 0991 treated group. Protein secondary structure was studied according to the composition of amide I band (1660 cm-1) and it demonstrated higher proportion of β-sheet structure as compared to α-helix in both studied groups.

  4. Cannabinoid receptors and their endogenous agonist, anandamide.

    PubMed

    Axelrod, J; Felder, C C

    1998-05-01

    Cannabinoids are a class of compound found in marijuana which have been known for their therapeutic and psychoactive properties for at least 4000 years. Isolation of the active principle in marijuana, delta9-THC, provided the lead structure in the development of highly potent congeners which were used to probe for the mechanism of marijuana action. Cannabinoids were shown to bind to selective binding sites in brain tissue thereby regulating second messenger formation. Such studies led to the cloning of three cannabinoid receptor subtypes, CB1, CB2, and CB1A all of which belong to the superfamily of G protein-coupled plasma membrane receptors. Analogous to the discovery of endogenous opiates, isolation of cannabinoid receptors provided the appropriate tool to isolate an endogenous cannabimimetic eicosanoid, anandamide, from porcine brain. Recent studies indicate that anandamide is a member of a family of fatty acid ethanolamides that may represent a novel class of lipid neurotransmitters. This review discusses recent progress in cannabinoid research with a focus on the receptors for delta9-THC, their coupling to second messenger responses, and the endogenous lipid cannabimimetic, anandamide.

  5. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  6. Modulation of P2 receptors on pancreatic β-cells by agonists and antagonists: a molecular target for type 2 diabetes treatment.

    PubMed

    Pacheco, Paulo Anastácio Furtado; Ferreira, Leonardo Gomes Braga; Alves, Luiz Anastacio; Faria, Robson Xavier

    2013-05-01

    Morbidity and mortality from diabetes mellitus (DM) are serious worldwide concerns. By the year 2030, the estimated number of diabetic patients will reach a staggering 439 million worldwide. Diabetes mellitus type 2 (DM2), which involves disturbances in both insulin secretion and resistance, is the most common form of diabetes and affects approximately 5 to 7% of the world's population. When a patient with DM2 cannot regulate his or her blood glucose levels through diet, weight loss, or exercise, oral medications, such as hypoglycemic agents (i.e., sulphonylureas, biguanides, alpha glucosidase inhibitors and thiazolidinediones), are crucial. Here, we discuss some physiological aspects of P2 receptors on pancreatic β-cells, which express a variety of P2 receptor isoforms. These receptors enhance glucose-dependent insulin release. In addition, we speculate on the potential of purinergic compounds as novel or additional treatments for Type 2 Diabetes mellitus.

  7. 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia.

    PubMed

    Rosenzweig-Lipson, Sharon; Comery, Thomas A; Marquis, Karen L; Gross, Jonathan; Dunlop, John

    2012-01-01

    The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.

  8. Saralasin and Sarile Are AT2 Receptor Agonists

    PubMed Central

    2014-01-01

    Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists. PMID:25313325

  9. Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist.

    PubMed

    Neilan, Claire L; Husbands, Stephen M; Breeden, Simon; Ko, M C Holden; Aceto, Mario D; Lewis, John W; Woods, James H; Traynor, John R

    2004-09-19

    The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. BU72 was a highly potent and long-lasting antinociceptive agent against both thermal and chemical nociception in the mouse and against thermal nociception in the monkey. These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.

  10. Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

    PubMed

    Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

    2009-06-01

    In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

  11. Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

    PubMed

    Williams, Wilbur P Trey; McLin, Dewey E; Dressman, Marlene A; Neubauer, David N

    2016-09-01

    Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

  12. Pharmacology of INS37217 [P(1)-(uridine 5')-P(4)- (2'-deoxycytidine 5')tetraphosphate, tetrasodium salt], a next-generation P2Y(2) receptor agonist for the treatment of cystic fibrosis.

    PubMed

    Yerxa, B R; Sabater, J R; Davis, C W; Stutts, M J; Lang-Furr, M; Picher, M; Jones, A C; Cowlen, M; Dougherty, R; Boyer, J; Abraham, W M; Boucher, R C

    2002-09-01

    INS37217 [P(1)-(uridine 5')-P(4)-(2'-deoxycytidine 5')tetraphosphate, tetrasodium salt] is a deoxycytidine-uridine dinucleotide with agonist activity at the P2Y(2) receptor. In primate lung tissues, the P2Y(2) receptor mRNA was located by in situ hybridization predominantly in epithelial cells and not in smooth muscle or stromal tissue. The pharmacologic profile of INS37217 parallels that of UTP, leading to increased chloride and water secretion, increased cilia beat frequency, and increased mucin release. The combined effect of these actions was confirmed in an animal model of tracheal mucus velocity that showed that a single administration of INS37217 significantly enhanced mucus transport for at least 8 h after dosing. This extended duration of action is consistent with the ability of INS37217 to resist metabolism by airway cells and sputum enzymes. The enhanced metabolic stability and resultant increased duration of improved mucociliary clearance may confer significant advantages to INS37217 over other P2Y(2) agonists in the treatment of diseases such as cystic fibrosis.

  13. Spirocyclic delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5747).

    PubMed

    Le Bourdonnec, Bertrand; Windh, Rolf T; Leister, Lara K; Zhou, Q Jean; Ajello, Christopher W; Gu, Minghua; Chu, Guo-Hua; Tuthill, Paul A; Barker, William M; Koblish, Michael; Wiant, Daniel D; Graczyk, Thomas M; Belanger, Serge; Cassel, Joel A; Feschenko, Marina S; Brogdon, Bernice L; Smith, Steven A; Derelanko, Michael J; Kutz, Steve; Little, Patrick J; DeHaven, Robert N; DeHaven-Hudkins, Diane L; Dolle, Roland E

    2009-09-24

    Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

  14. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor*

    PubMed Central

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J.; Wolber, Gerhard; Mohr, Klaus

    2016-01-01

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  15. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    PubMed

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo; Taheri, Masoumeh; Komaki, Hamidreza; Etaee, Farshid

    2017-04-01

    Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB1/CB2) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB1/CB2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

  16. Interleukin-24 as a target cytokine of environmental aryl hydrocarbon receptor agonist exposure in the lung.

    PubMed

    Luo, Yueh-Hsia; Kuo, Yu-Chun; Tsai, Ming-Hsien; Ho, Chia-Chi; Tsai, Hui-Ti; Hsu, Chin-Yu; Chen, Yu-Cheng; Lin, Pinpin

    2017-06-01

    Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Covalent agonists for studying G protein-coupled receptor activation

    PubMed Central

    Weichert, Dietmar; Kruse, Andrew C.; Manglik, Aashish; Hiller, Christine; Zhang, Cheng; Hübner, Harald; Kobilka, Brian K.; Gmeiner, Peter

    2014-01-01

    Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis. PMID:25006259

  18. Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization

    PubMed Central

    Virk, Michael S.; Arttamangkul, Seksiri; Birdsong, William T.; Williams, John T.

    2009-01-01

    Buprenorphine is a weak partial agonist at mu-opioid receptors that is used for treatment of pain and addiction. Intracellular and whole cell recordings were made from locus coeruleus (LC) neurons in rat brain slices to characterize the actions of buprenorphine. Acute application of buprenorphine caused a hyperpolarization that was prevented by previous treatment of slices with the irreversible opioid antagonist, β-chlornaltrexamine (β-CNA), but was not reversed by a saturating concentration of naloxone. As expected for a partial agonist, sub-saturating concentrations of buprenorphine decreased the [Met]5 enkephalin (ME) induced hyperpolarization or outward current. When the ME induced current was decreased below a critical value, desensitization and internalization of μ-opioid receptors (MOR) was eliminated. The inhibition of desensitization by buprenorphine was not the result of prior desensitization, slow dissociation from the receptor, or elimination of receptor reserve. Treatment of slices with sub-saturating concentrations of etorphine, methadone, oxymorphone or β-CNA also reduced the current induced by ME but did not block ME-induced desensitization. Treatment of animals with buprenorphine for a week resulted in the inhibition of the current induced by ME and a block of desensitization that was not different from the acute application of buprenorphine to brain slices. These observations show the unique characteristics of buprenorphine and further demonstrate the range of agonist selective actions that are possible through G-protein coupled receptors. PMID:19494155

  19. The Efficacy of Pramipexole, a Dopamine Receptor Agonist, as an Adjunctive Treatment in Treatment-Resistant Depression: An Open-Label Trial

    PubMed Central

    Hori, Hiroaki; Kunugi, Hiroshi

    2012-01-01

    Dopaminergic dysfunction is implicated in the pathophysiology of treatment-resistant depression. Although the efficacy of adjunctive pramipexole treatment has been demonstrated in treatment-resistant bipolar depression, such data are scarce for major depressive disorder (MDD). We recruited 17 patients with DSM-IV major depressive episode who have failed to respond to previous treatment with a selective serotonin reuptake inhibitor. Five patients were diagnosed as having bipolar II disorder and 12 as having unipolar MDD. Patients were monitored at an ambulatory care facility every two weeks until 12 weeks. Pramipexole was added to existing medication. Depression severity was assessed with the Hamilton Depression Rating Scale 21-item version (HDRS-21). The mean maximum dosage of pramipexole was 1.6 mg (SD 0.9). The HDRS-21 total score decreased from 19.4 (SD 3.8) at baseline to 7.2 (SD 5.4) at endpoint (P < 0.000001). Twelve patients (71%) were responders based on the definition of 50% or more reduction in the HDRS-21 score. Ten patients (59%) remitted (HDRS-21 total score at endpoint <8). These results were almost unchanged when the sample was confined to patients with MDD. No serious adverse events were observed. Our findings indicate that pramipexole augmentation therapy may be effective and well tolerated in refractory depressed patients. PMID:22919308

  20. Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors

    PubMed Central

    Wood, Martyn; Dubois, Vanessa; Scheller, Dieter; Gillard, Michel

    2015-01-01

    Background and Purpose Rotigotine acts as a dopamine receptor agonist with high affinity for the dopamine D2, D3, D4 and D5 receptors but with a low affinity for the dopamine D1 receptor. We have investigated this further in radioligand binding and functional studies and compared the profile of rotigotine with that of other drugs used in the treatment of Parkinson's disease (PD). Experimental Approach The binding of rotigotine to human dopamine D1, D2, D3, D4 and D5 receptors was determined in radioligand binding studies using [3H]rotigotine and compared with that of standard antagonist radioligands. Functional interactions of rotigotine with human dopamine receptors was also determined. Key Results [3H]rotigotine can be used as an agonist radioligand to label all dopamine receptor subtypes and this can be important to derive agonist affinity estimates. Rotigotine maintains this high affinity in functional studies at all dopamine receptors especially D1, D2 and D3 receptors and, to a lesser extent, D4 and D5 receptors. Rotigotine, like apomorphine but unlike ropinirole and pramipexole, was a potent agonist at all dopamine receptors. Conclusions and Implications Rotigotine is a high-potency agonist at human dopamine D1, D2 and D3 receptors with a lower potency at D4 and D5 receptors. These studies differentiate rotigotine from conventional dopamine D2 agonists, used in the treatment of PD, such as ropinirole and pramipexole which lack activity at the D1 and D5 receptors, but resembles that of apomorphine which has greater efficacy in PD than other dopamine agonists but has suboptimal pharmacokinetic properties. PMID:25339241

  1. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    PubMed Central

    Pertwee, R.G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors. PMID:20166927

  2. Thrombopoietin-receptor agonists in haematological disorders: the Danish experience.

    PubMed

    Gudbrandsdottir, Sif; Frederiksen, Henrik; Hasselbalch, Hans

    2012-01-01

    The objective of this study was to investigate the use of thrombopoietin-receptor agonists (TPO-ra) in patients with refractory primary immune thrombocytopenia (ITP) as well as off-label use of TPO-ra in Danish haematology departments. Hospital medical records from 32 of the 39 patients having received TPO-ra from 2009 to 1 May 2011 were available for data collection and included in the study. Of these patients, 15 received TPO-ra for refractory primary ITP, 7 for secondary ITP (chronic lymphatic leukaemia, systemic lupus erythematosus, Evans syndrome, human immunodeficiency virus and celiac disease) and 10 were treated for non-ITP (chemotherapy-induced, acute myeloid leukaemia, myelodysplastic syndrome, hereditary spherocytosis and suspected chemically induced thrombocytopenia). Initial response to TPO-ra defined as platelet counts >30 × 10(9)/l after 4 weeks of treatment was found in 59% of primary ITP patients, 57% of patients with secondary ITP and 40% of patients with non-ITP. There were four deaths in the cohort, three of which were related to pre-existing medical conditions. Otherwise adverse effects were in general mild. This Danish retrospective registration study has demonstrated that in the off-protocol setting, the use of TPO-ra is associated with response rates largely similar to those seen in previous protocol-monitored studies and no new adverse events were reported.

  3. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  4. Glucagon-like peptide-1 receptors agonists (GLP1 RA).

    PubMed

    Kalra, Sanjay

    2013-10-01

    The glucagon-like peptide-1 receptors agonists (GLP1RA) are a relatively new class of drugs, used for management of type 2 diabetes. This review studies the characteristics of these drugs, focusing upon their mechanism of action, intra-class differences, and utility in clinical practice. It compares them with other incretin based therapies, the dipeptidyl peptidase-IV inhibitors, and predicts future developments in the use of these molecules, while highlighting the robust indications for the use of these drugs.

  5. Pharmacological and functional characterization of novel EP and DP receptor agonists: DP1 receptor mediates penile erection in multiple species.

    PubMed

    Brugger, Nadia; Kim, Noel N; Araldi, Gian Luca; Traish, Abdulmaged M; Palmer, Stephen S

    2008-02-01

    Despite the widespread use of prostaglandin E(1) as an efficacious treatment for male erectile dysfunction for more than two decades, research on prostanoid function in penile physiology has been limited. To characterize the pharmacological and physiological activity of novel subtype-selective EP and DP receptor agonists. Radioligand binding and second messenger assays were used to define receptor subtype specificity of the EP and DP agonists. Functional activity was further characterized using isolated human and rabbit penile cavernosal tissue in organ baths. In vivo activity was assessed in rabbits and rats by measuring changes in cavernous pressure after intracavernosal injection of receptor agonists. Receptor binding and signal transduction, smooth muscle contractile activity, erectile function. In organ bath preparations of human cavernosal tissue contracted with phenylephrine, EP2- and EP4-selective agonists exhibited variable potency in causing relaxation. One of the compounds caused mild contraction, and none of the compounds was as effective as PGE(1) (EC(50) = 0.23 microM). There was no consistent correlation between the pharmacological profile (receptor binding and second messenger assays) of the EP agonists and their effect on cavernosal tissue tone. In contrast, the DP1-selective agonist AS702224 (EC(50) =29 nM) was more effective in relaxing human cavernosal tissue than either PGE(1), PGD(2) (EC(50) = 58 nM), or the DP agonist BW245C (EC(50) =59 nM). In rabbit cavernosal tissue, PGE(1) and PGD(2) caused only contraction, while AS702224 and BW245C caused relaxation. Intracavernosal administration of AS702224 and BW245C also caused penile tumescence in rabbits and rats. For each compound, the erectile response improved with increasing dose and was significantly higher than vehicle alone. These data suggest that AS702224 is a potent DP1-selective agonist that causes penile erection. The DP1 receptor mediates relaxation in human cavernosal tissue, and

  6. The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors.

    PubMed

    Wierucka-Rybak, M; Wolak, M; Juszczak, M; Drobnik, J; Bojanowska, E

    2016-06-01

    Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects. These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.

  7. Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats.

    PubMed

    Huizenga, Megan N; Wicker, Evan; Beck, Veronica C; Forcelli, Patrick A

    2017-09-01

    Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates. We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats. Postnatal day (P) 10, Sprague-Dawley rat pups were challenged with the chemoconvulsant methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) or pentylenetetrazole (PTZ), after treatment with either CB1/2 mixed agonist (WIN 55,212-2), CB1 agonist (arachidonyl-2'-chloroethylamide [ACEA]), CB2 agonist (HU-308), CB1 antagonist (AM-251), CB2 antagonist (AM-630), fatty acid amide hydrolase inhibitor (URB-597), or G protein-coupled receptor 55 agonist (O-1602). P20 Sprague-Dawley pups were challenged with DMCM after treatment with WIN, ACEA, or URB. Finally, after pretreatment with WIN, P10 Sprague-Dawley rats were challenged against acute hypoxia-induced seizures. The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ. Anticonvulsant effects were seen in P10 animals but not P20 animals. Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. These data indicate that the anticonvulsant action of the CB system is specific to CB1

  8. G-protein mediates voltage regulation of agonist binding to muscarinic receptors: effects on receptor-Na/sup +/ channel interaction

    SciTech Connect

    Cohen-Armon, M.; Garty, H.; Sokolovsky, M.

    1988-01-12

    The authors previous experiments in membranes prepared from rat heart and brain led them to suggest that the binding of agonist to the muscarinic receptors and to the Na/sup +/ channels is a coupled event mediated by guanine nucleotide binding protein(s) (G-protein(s)). These in vitro findings prompted us to employ synaptoneurosomes from brain stem tissue to examine (i) the binding properties of (/sup 3/H) acetylcholine at resting potential and under depolarization conditions in the absence and presence of pertussis toxin; (ii) the binding of (/sup 3/H)batrachotoxin to Na/sup +/ channel(s) in the presence of the muscarinic agonists; and (iii) muscarinically induced /sup 22/Na/sup +/ uptake in the presence and absence of tetrodotoxin, which blocks Na/sup +/ channels. The findings indicate that agonist binding to muscarinic receptors is voltage dependent, that this process is mediated by G-protein(s), and that muscarinic agonists induce opening of Na/sup +/channels. The latter process persists even after pertussis toxin treatment, indicating that it is not likely to be mediated by pertussis toxin sensitive G-protein(s). The system with its three interacting components-receptor, G-protein, and Na/sup +/ channel-is such that at resting potential the muscarinic receptor induces opening of Na/sup +/ channels; this property may provide a possible physiological mechanism for the depolarization stimulus necessary for autoexcitation or repetitive firing in heart or brain tissues.

  9. MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models

    PubMed Central

    Naguib, M; Diaz, P; Xu, J J; Astruc-Diaz, F; Craig, S; Vivas-Mejia, P; Brown, D L

    2008-01-01

    Background and purpose: There is growing interest in using cannabinoid type 2 (CB2) receptor agonists for the treatment of neuropathic pain. In this report, we describe the pharmacological characteristics of MDA7 (1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl]piperidine), a novel CB2 receptor agonist. Experimental approach: We characterized the pharmacological profile of MDA7 by using radioligand-binding assays and in vitro functional assays at human cannabinoid type 1 (CB1) and CB2 receptors. In vitro functional assays were performed at rat CB1 and CB2 receptors. The effects of MDA7 in reversing neuropathic pain were assessed in spinal nerve ligation and paclitaxel-induced neuropathy models in rats. Key results: MDA7 exhibited selectivity and agonist affinity at human and rat CB2 receptors. MDA7 treatment attenuated tactile allodynia produced by spinal nerve ligation or by paclitaxel in a dose-related manner. These effects were selectively antagonized by a CB2 receptor antagonist but not by CB1 or opioid receptor antagonists. MDA7 did not affect rat locomotor activity. Conclusion and implications: MDA7, a novel selective CB2 agonist, was effective in suppressing neuropathic nociception in two rat models without affecting locomotor behaviour. These results confirm the potential for CB2 agonists in the treatment of neuropathic pain. PMID:18846037

  10. Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task.

    PubMed

    Perez-García, Georgina S; Meneses, A

    2005-08-30

    This work aimed to evaluate further the role of 5-HT7 receptors during memory formation in an autoshaping Pavlovian/instrumental learning task. Post-training administration of the potential 5-HT7 receptor agonist AS 19 or antagonist SB-269970 enhanced memory formation or had no effect, respectively. The AS 19 facilitatory effect was reversed by SB-269970, but not by the selective 5-HT1A antagonist WAY100635. Amnesia induced by scopolamine (cholinergic antagonist) or dizocilpine (NMDA antagonist) was also reversed by AS 19. Certainly, reservations regarding the selectivity of AS 19 for 5-HT7 and other 5-HT receptors in vivo are noteworthy and, therefore, its validity for use in animal models as a pharmacological tool. Having mentioned that, it should be noticed that together these data are providing further support to the notion of the 5-HT7 receptors role in memory formation. Importantly, this 5-HT7 receptor agonist AS 19 appears to represent a step forward respect to the notion that potent and selective 5-HT7 receptor agonists can be useful in the treatment of dysfunctional memory in aged-related decline and Alzheimer's disease.

  11. Evaluation of peroxisome proliferator-activated receptor agonists on interleukin-5-induced eosinophil differentiation

    PubMed Central

    Smith, Steven G; Hill, Mike; Oliveria, John-Paul; Watson, Brittany M; Baatjes, Adrian J; Dua, Benny; Howie, Karen; Campbell, Heather; Watson, Rick M; Sehmi, Roma; Gauvreau, Gail M

    2014-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) -induced eosinophil differentiation from haemopoietic progenitor cells. Non-adherent mononuclear cells or CD34+ cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult® cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1–1000 nm PPARα agonist (GW9578), PPARβ/δ agonist (GW501516), PPARγ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34+ cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal-regulated kinase 1/2 signalling pathway. These findings indicate that the PPARγ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses. PMID:24628018

  12. Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

    PubMed Central

    Fierro, Fabrizio; Suku, Eda; Alfonso-Prieto, Mercedes; Giorgetti, Alejandro; Cichon, Sven; Carloni, Paolo

    2017-01-01

    Human G-protein coupled receptors (hGPCRs) constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation. PMID:28932739

  13. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    SciTech Connect

    Di Paolo, T.; Falardeau, P.

    1987-08-31

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p < 0.001). Competition for (/sup 3/H)-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-(..beta..-..gamma..-imino)triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables.

  14. hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma

    PubMed Central

    Fleten, Karianne G; Flørenes, Vivi Ann; Prasmickaite, Lina; Hill, Oliver; Sykora, Jaromir; Mælandsmo, Gunhild M; Engesæter, Birgit

    2016-01-01

    In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients. PMID:28028438

  15. hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma.

    PubMed

    Fleten, Karianne G; Flørenes, Vivi Ann; Prasmickaite, Lina; Hill, Oliver; Sykora, Jaromir; Mælandsmo, Gunhild M; Engesæter, Birgit

    2016-01-01

    In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.

  16. Identification of agonists for a group of human odorant receptors

    PubMed Central

    Gonzalez-Kristeller, Daniela C.; do Nascimento, João B. P.; Galante, Pedro A. F.; Malnic, Bettina

    2015-01-01

    Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs) which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10%) have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs. PMID:25784876

  17. Luteinizing hormone-releasing hormone agonists in premenopausal hormone receptor-positive breast cancer.

    PubMed

    Tan, Sing-Huang; Wolff, Antonio C

    2007-02-01

    Ovarian function suppression for the treatment of premenopausal breast cancer was first used in the late 19th century. Traditionally, ovarian function suppression had been accomplished irreversibly via irradiation or surgery, but analogues of the luteinizing hormone-releasing hormone (LH-RH) have emerged as reliable and reversible agents for this purpose, especially the LH-RH agonists. Luteinizing hormone-releasing hormone antagonists are in earlier stages of development in breast cancer and are not currently in clinical use. Luteinizing hormonereleasing hormone agonists act by pituitary desensitization and receptor downregulation, thereby suppressing gonadotrophin release. Limited information is available comparing the efficacies of the depot preparations of various agonists, but pharmacodynamic studies have shown comparable suppressive capabilities on estradiol and luteinizing hormone. At present, only monthly goserelin is Food and Drug Administration-approved for the treatment of estrogen receptor-positive, premenopausal metastatic breast cancer in the United States. Luteinizing hormone-releasing hormone agonists have proven to be as effective as surgical oophorectomy in premenopausal advanced breast cancer. They offer similar outcomes compared with tamoxifen, but the endocrine combination appears to be more effective than LH-RH agonists alone. In the adjuvant setting, LH-RH agonists versus no therapy reduce the annual odds of recurrence and death in women aged>50 years with estrogen receptor-positive tumors. Luteinizing hormone-releasing hormone agonists alone or in combination with tamoxifen have shown disease-free survival rates similar to chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil). Outcomes of chemotherapy with or without LH-RH agonists are comparable, though a few trials favor the combination in young premenopausal women (aged<40 years). Adjuvant LH-RH agonists with or without tamoxifen might be as efficacious as tamoxifen alone

  18. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

    PubMed

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

    2016-02-15

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

  19. Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer.

    PubMed

    Liu, Jinyou; Viswanadhapalli, Suryavathi; Garcia, Lauren; Zhou, Mei; Nair, Binoj C; Kost, Edward; Rao Tekmal, Rajeshwar; Li, Rong; Rao, Manjeet K; Curiel, Tyler; Vadlamudi, Ratna K; Sareddy, Gangadhara R

    2017-07-25

    Ovarian cancer is the deadliest of all gynecologic cancers. Despite success with initial chemotherapy, the majority of patients relapse with an incurable disease. Development of chemotherapy resistance is a major factor for poor long-term survival in ovarian cancer. The biological effects of estrogens are mediated by estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Emerging evidence suggests that ovarian cancer cells express ERβ that functions as a tumor suppressor; however, the clinical utility of ERβ agonists in ovarian cancer remains elusive. We tested the utility of two natural ERβ agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer. Both natural ERβ ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERβ agonists showed tumor suppressive functions in therapy-resistant ovarian cancer model cells and sensitized ovarian cancer cells to cisplatin and paclitaxel treatment. Global RNA-Seq analysis revealed that ERβ agonists modulate several tumor suppressive pathways, including downregulation of the NF-κB pathway. Immunoprecipitation assays revealed that ERβ interacts with p65 subunit of NF-κB and ERβ overexpression reduced the expression of NF-κB target genes. In xenograft assays, ERβ agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERβ agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERβ agonists represent novel therapeutic agents for the management of ovarian cancer.

  20. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

    PubMed Central

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C.; Hershfeld, Alena; Kenyon, Lawrence C.

    2015-01-01

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K+ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

  1. Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

    PubMed Central

    Vang, Derek; Paul, Jinny A.; Nguyen, Julia; Tran, Huy; Vincent, Lucile; Yasuda, Dennis; Zaveri, Nurulain T.; Gupta, Kalpna

    2015-01-01

    Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia. PMID:26294734

  2. Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice.

    PubMed

    Vang, Derek; Paul, Jinny A; Nguyen, Julia; Tran, Huy; Vincent, Lucile; Yasuda, Dennis; Zaveri, Nurulain T; Gupta, Kalpna

    2015-12-01

    Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia. Copyright© Ferrata Storti Foundation.

  3. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

    PubMed

    Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.

  4. The binding properties of the muscarinic receptors of the cynomolgus monkey ciliary body and the response to the induction of agonist subsensitivity.

    PubMed Central

    Bárány, E.; Berrie, C. P.; Birdsall, N. J.; Burgen, A. S.; Hulme, E. C.

    1982-01-01

    1 The binding properties of the muscarinic receptors in the ciliary muscle of cynomolgus monkeys have been evaluated. 2 The concentration of receptor binding sites is the highest yet reported. As found in many species and tissues, there are subclasses of agonist binding sites. Agonist binding is not affected by the non-hydrolysable guanosine triphosphate (GTP) analogue, GppNHp, suggesting that these receptors are not linked to adenylate cyclase. 3 Ciliary muscles made subsensitive by treatment with muscarinic agonists have a decreased receptor concentration but no other changes in the binding properties of the receptors could be detected. PMID:6897523

  5. A rationally designed agonist defines subfamily IIIA ABA receptors as critical targets for manipulating transpiration.

    PubMed

    Vaidya, Aditya S; Peterson, Francis C; Yarmolinsky, Dmitry; Merilo, Ebe; Verstraeten, Inge; Park, Sang-Youl; Elzinga, Dezi; Kaundal, Amita; Helander, Jonathan; Lozano-Juste, Jorge; Otani, Masato; Wu, Kevin; Jensen, Davin R; Kollist, Hannes; Volkman, Brian F; Cutler, Sean R

    2017-09-26

    Increasing drought and diminishing freshwater supplies have stimulated interest in developing chemicals that can be used to control transpiration. Receptors for the plant hormone abscisic acid (ABA) have emerged as key targets for this application, because ABA controls the apertures of stomata, which in turn regulate transpiration. Here we describe the rational design of cyanabactin, an ABA receptor agonist that preferentially activates Pyrabactin resistance 1 (PYR1) with low nM potency. A 1.63 Å X-ray crystallographic structure of cyanabactin in complex with PYR1 illustrates that cyanabactin's arylnitrile mimics ABA's cyclohexenone oxygen and engages the tryptophan lock, a key component required to stabilize activated receptors. Further, its sulfonamide and 4-methylbenzyl substructures mimic ABA's carboxylate and C-6 methyl groups respectively. Isothermal titration calorimetry measurements show that cyanabactin's compact structure provides ready access to high ligand efficiency on a relatively simple scaffold. Cyanabactin treatments reduce Arabidopsis whole-plant stomatal conductance and activate multiple ABA responses, demonstrating that its in vitro potency translates to ABA-like activity in vivo. Genetic analyses show that the effects of cyanabactin, and the previously identified agonist quinabactin, can be abolished by genetic removal of PYR1 and PYL1, which form subclade A within the dimeric subfamily III receptors. Thus, cyanabactin is a potent and selective agonist with wide-spectrum ABA-like activity that defines subfamily IIIA receptors as key target sites for manipulating transpiration.

  6. Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ.

    PubMed

    dos Santos, Jademilson Celestino; Bernardes, Amanda; Giampietro, Letizia; Ammazzalorso, Alessandra; De Filippis, Barbara; Amoroso, Rosa; Polikarpov, Igor

    2015-09-01

    Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARγ is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARα ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARα/γ agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARα and PPARγ receptors. GL479 was previously reported as a partial agonist of PPARγ and a full agonist of PPARα with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARα and PPARγ, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARα, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARγ displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARα/γ agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders.

    PubMed

    Laudon, Moshe; Frydman-Marom, Anat

    2014-09-09

    Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions.

  8. Therapeutic Effects of Melatonin Receptor Agonists on Sleep and Comorbid Disorders

    PubMed Central

    Laudon, Moshe; Frydman-Marom, Anat

    2014-01-01

    Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions. PMID:25207602

  9. Interaction of a radiolabeled agonist with cardiac muscarinic cholinergic receptors

    SciTech Connect

    Harden, T.K.; Meeker, R.B.; Martin, M.W.

    1983-12-01

    The interaction of a radiolabeled muscarinic cholinergic receptor agonist, (methyl-/sup 3/H)oxotremorine acetate ((/sup 3/H)OXO), with a washed membrane preparation derived from rat heart, has been studied. In binding assays at 4 degrees C, the rate constants for association and dissociation of (/sup 3/H)OXO were 2 X 10(7) M-1 min-1 and 5 X 10(-3) min-1, respectively, Saturation binding isotherms indicated that binding was to a single population of sites with a Kd of approximately 300 pM. The density of (/sup 3/H)OXO binding sites (90-100 fmol/mg of protein) was approximately 75% of that determined for the radiolabeled receptor antagonist (/sup 3/H)quinuclidinyl benzilate. Both muscarinic receptor agonists and antagonists inhibited the binding of (/sup 3/H)OXO with high affinity and Hill slopes of approximately one. Guanine nucleotides completely inhibited the binding of (/sup 3/H)OXO. This effect was on the maximum binding (Bmax) of (/sup 3/H)OXO with no change occurring in the Kd; the order of potency for five nucleotides was guanosine 5'-O-(3-thio-triphosphate) greater than 5'-guanylylimidodiphosphate greater than GTP greater than or equal to guanosine/diphosphate greater than GMP. The (/sup 3/H)OXO-induced interaction of muscarinic receptors with a guanine nucleotide binding protein was stable to solubilization. That is, membrane receptors that were prelabeled with (/sup 3/H)OXO could be solubilized with digitonin, and the addition of guanine nucleotides to the soluble, (/sup 3/H)OXO-labeled complex resulted in dissociation of (/sup 3/H)OXO from the receptor. Pretreatment of membranes with relatively low concentrations of N-ethylmaleimide inhibited (/sup 3/H)OXO binding by 85% with no change in the Kd of (/sup 3/H)OXO, and with no effect on (/sup 3/H)quinuclidinyl benzilate binding.

  10. Metabolic mapping of A3 adenosine receptor agonist MRS5980.

    PubMed

    Fang, Zhong-Ze; Tosh, Dilip K; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W; O'Connor, Robert; Jacobson, Kenneth A; Gonzalez, Frank J

    2015-09-15

    (1S,2R,3S,4R,5S)-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is an A3AR selective agonist containing multiple receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC-MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A3AR, considering efficacy, metabolic elimination, and

  11. Metabolic mapping of A3 adenosine receptor agonist MRS5980

    PubMed Central

    Fang, Zhong-Ze; Tosh, Dilip K.; Tanaka, Naoki; Wang, Haina; Krausz, Kristopher W.; O'Connor, Robert; Jacobson, Kenneth A.; Gonzalez, Frank J.

    2015-01-01

    (1S,2R,3S,4R,5S)-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is an A3AR selective agonist containing multiple receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason of drug R&D failure. Metabolomics with UPLC-MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment group in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation for feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the major involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A3AR, considering efficacy, metabolic elimination, and

  12. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver

    PubMed Central

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis. PMID:26770990

  13. Central- and peripheral-type benzodiazepine receptors: similar regulation by stress and GABA receptor agonists.

    PubMed

    Rägo, L; Kiivet, R A; Harro, J; Pŏld, M

    1989-04-01

    Central- and peripheral-type benzodiazepine (BD) receptors were labelled either by 3H-flunitrazepam or 3H-Ro 5-4864 in vitro after stress and in vivo administration of GABAA and GABAB agonists. A significant increase in the density of cerebral cortex and kidney BD binding sites was observed in rats after forced swimming stress. Similar changes in both type of BD receptors were also followed when naive (stressed) and handling-habituated (unstressed) rats were used. Stress in both models was unable to change the affinity of BD receptors in cerebral cortex, but significantly lowered it in kidneys. Acute treatment of rats with muscimol (1.5 mg/kg) or (-)baclofen (5 mg/kg) resulted in marked increase in the affinity of BD binding not only in cerebral cortex but also in kidneys. After (-)baclofen treatment the number of BD binding sites was lowered in the structures studied. In a separate study mice selected according to their behavioral response to (-)baclofen (1 mg/kg) were studied. Two weeks after the selection it appeared that baclofen responders were behaviorally more "anxious" than baclofen nonresponders. The number of BD binding sites was reduced in cerebral cortex, cerebellum, heart and kidneys in baclofen responders as compared to baclofen nonresponders. In several cases the changes in peripheral BD binding sites were even more pronounced than those in central ones. The data presented here evidence that peripheral- and central-type BD receptors are regulated similarly by GABA and some models of stress. The physiological mechanisms involved in similar regulation of central- and peripheral-type BD receptors are yet unknown.

  14. Agonist Derived Molecular Probes for A2A Adenosine Receptors

    PubMed Central

    Jacobson, Kenneth A.; Pannell, Lewis K.; Ji, Xiao-duo; Jarvis, Michael F.; Williams, Michael; Hutchison, Alan J.; Barrington, William W.; Stiles, Gary L.

    2011-01-01

    The adenosine agonist 2-(4-(2-carboxyethyl)phenylethylamino)-5′-N-ethylcarboxamidoadenosine (CGS21680) was recently reported to be selective for the A2A adenosine receptor subtype, which mediates its hypotensive action. To investigate structurelactivity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p-hydroxyphenylpropionic, 2-thiophenylacetic, and p-aminophenylacetic acids were prepared. The latter derivative (PAPA-APEC) was iodinated electrophilically using [125I]iodide resulting in a radioligand which was used for studies of competition of binding to striatal A, adenosine receptors in bovine brain. A biotin conjugate and an aryl sulfonate were at least 350-fold selective for A, receptors. For spectroscopic detection, a derivative of the stable free radical tetramethyl-1-piperidinyloxy (TEMPO) was prepared. For irreversible inhibition of receptors, meta- and para-phenylenediisothiocyanate groups were incorporated in the analogs. We have demonstrated that binding at A2A receptors is relatively insensitive to distal structural changes at the 2-position, and we report high affinity molecular probes for receptor characterization by radioactive, spectroscopic and affinity labelling methodology. PMID:2561548

  15. A delayed and chronic treatment regimen with the 5-HT1A receptor agonist 8-OH-DPAT after cortical impact injury facilitates motor recovery and acquisition of spatial learning

    PubMed Central

    Cheng, Jeffrey P.; Hoffman, Ann N.; Zafonte, Ross D.; Kline, Anthony E.

    2008-01-01

    An early (i.e., 15 min) single systemic administration of the 5-HT1A receptor agonist 8-OH-DPAT enhances behavioral recovery after experimental traumatic brain injury (TBI). However, acute administration of pharmacotherapies after TBI may be clinically challenging and thus the present study sought to investigate the potential efficacy of a delayed and chronic 8-OH-DPAT treatment regimen. Forty-eight isoflurane-anesthetized adult male rats received either a controlled cortical impact or sham injury and beginning 24 hrs later were administered 8-OH-DPAT (0.1 or 0.5 mg/kg) or saline vehicle (1.0 mL/kg) intraperitoneally once daily until all behavioral assessments were completed. Neurobehavior was assessed by motor and cognitive tests on post-operative days 1–5 and 14–19, respectively. The lower dose of 8-OH-DPAT (0.1 mg/kg) enhanced motor performance, acquisition of spatial learning, and memory retention vs. both the higher dose (0.5 mg/kg) and vehicle treatment (p < 0.05). These data replicate previous findings from our laboratory showing that 8-OH-DPAT improves neurobehavior after TBI, and extend those results by demonstrating that the benefits can be achieved even when treatment is withheld for 24 hrs. A delayed and chronic treatment regimen may be more clinically feasible. PMID:18638506

  16. Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

    PubMed Central

    Bohonowych, Jessica E. S.; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T.; Denison, Michael S.

    2010-01-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [3H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  17. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed.

  18. Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity-related metabolic disease.

    PubMed

    Abegg, Kathrin; Bernasconi, Lara; Hutter, Melanie; Whiting, Lynda; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2017-05-24

    Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2. In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids. Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice. Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus. © 2017 John Wiley & Sons Ltd.

  19. Thyroid Hormone Receptor Agonists Reduce Serum Cholesterol Independent of the LDL Receptor

    PubMed Central

    Lin, Jean Z.; Martagón, Alexandro J.; Hsueh, Willa A.; Baxter, John D.; Gustafsson, Jan-Åke; Webb, Paul

    2012-01-01

    The majority of cholesterol reduction therapies, such as the statin drugs, work primarily by inducing the expression of hepatic low-density lipoprotein receptors (LDLRs), rendering these therapeutics only partially effective in animals lacking LDLRs. Although thyroid hormones and their synthetic derivatives, often referred to as thyromimetics, have been clearly shown to reduce serum cholesterol levels, this action has generally been attributed to their ability to increase expression of hepatic LDLRs. Here we show for the first time that the thyroid hormone T3 and the thyroid hormone receptor-β selective agonists GC-1 and KB2115 are capable of markedly reducing serum cholesterol in mice devoid of functional LDLRs by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Based on this LDLR-independent mechanism, thyromimetics such as GC-1 and KB2115 may represent promising cholesterol-lowering therapeutics for the treatment of diseases such as homozygous familial hypercholesterolemia, a rare genetic disorder caused by a complete lack of functional LDLRs, for which there are limited treatment options because most therapeutics are only minimally effective. PMID:23087171

  20. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

    PubMed

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-08-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

  1. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist

    PubMed Central

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-01-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury. PMID:26196013

  2. β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

    PubMed

    Vijftigschild, Lodewijk A W; Berkers, Gitte; Dekkers, Johanna F; Zomer-van Ommen, Domenique D; Matthes, Elizabeth; Kruisselbrink, Evelien; Vonk, Annelotte; Hensen, Chantal E; Heida-Michel, Sabine; Geerdink, Margot; Janssens, Hettie M; van de Graaf, Eduard A; Bronsveld, Inez; de Winter-de Groot, Karin M; Majoor, Christof J; Heijerman, Harry G M; de Jonge, Hugo R; Hanrahan, John W; van der Ent, Cornelis K; Beekman, Jeffrey M

    2016-09-01

    We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

  3. Melatonin attenuates the development of antinociceptive tolerance to delta-, but not to mu-opioid receptor agonist in mice.

    PubMed

    Dai, Xu; Cui, Shi-gang; Li, Shi-rong; Chen, Qiang; Wang, Rui

    2007-08-22

    The effects of melatonin (Mel) on the development of tolerance to antinociceptive actions induced by mu- and delta-opioid receptor agonists were determined in male Kunming mice. In the mouse tail-flick tests, selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly, i.c.v.) in the absence or presence of melatonin. Administration of endomorphin-1 (EM-1, a mu-opioid receptor agonist) or deltorphin I (del I, a delta-opioid receptor agonist) twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls. Co-administration with melatonin prevented the development of tolerance to deltorphin I analgesia, and this effect was dose dependent. However, melatonin did not affect the development of antinociceptive tolerance to endomorphin-1. Additionally, the attenuation of deltorphin I tolerance by melatonin was reduced by chronic treatment with luzindole (luz), a selective antagonist on the MT(2) receptor subtype. Taken together, these data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta-opioid agonist analgesia via its receptor.

  4. Efficacy and safety of insulin-GLP-1 receptor agonists combination in type 2 diabetes mellitus: a systematic review.

    PubMed

    Cimmaruta, D; Maiorino, M I; Scavone, C; Sportiello, L; Rossi, F; Giugliano, D; Esposito, K; Capuano, A

    2016-12-01

    Attaining optimal glycemic targets in patients with type 2 diabetes is often hard and compromised by the shortcomings of the several treatments. Areas covered: When glycemic levels are not adequately controlled, an association of GLP-1 receptor agonists and insulin therapy can be adopted. In order to assess the benefit/risk profile of this combination therapy, a literature search of randomized clinical trials was performed.Eighteen trials matched the inclusion criteria. In 10 studies, GLP-1 receptor agonists were added on to an existing regimen, whereas insulin added to an existing GLP-1 receptor agonists regimen occurred in 2 studies. Six studies compared GLP-1 receptor agonists with short acting insulin as a treatment strategy to intensify basal insulin therapy. Expert opinion: Clinical trials herein reviewed demonstrated the safety and the efficacy of combining GLP-1 receptor agonists with basal insulin, with most studies showing equal or slightly superior efficacy, as compared with the addition of prandial insulin, associated with weight loss and less hypoglycemia.

  5. Short-term desensitization of muscarinic cholinergic receptors in mouse neuroblastoma cells: selective loss of agonist low-affinity and pirenzepine high-affinity binding sites

    SciTech Connect

    Cioffi, C.L.; el-Fakahany, E.E.

    1986-09-01

    The effects of brief incubation with carbamylcholine on subsequent binding of (/sup 3/H)N-methylscopolamine were investigated in mouse neuroblastoma cells (clone N1E-115). This treatment demonstrated that the muscarinic receptors in this neuronal clone can be divided into two types; one which is readily susceptible to regulation by receptor agonists, whereas the other is resistant in this regard. In control cells, both pirenzepine and carbamylcholine interacted with high- and low-affinity subsets of muscarinic receptors. Computer-assisted analysis of the competition between pirenzepine and carbamylcholine with (/sup 3/H)N-methylscopolamine showed that the receptor sites remaining upon desensitization are composed mainly of pirenzepine low-affinity and agonist high-affinity binding sites. Furthermore, there was an excellent correlation between the ability of various muscarinic receptor agonists to induce a decrease in consequent (/sup 3/H)N-methylscopolamine binding and their efficacy in stimulating cyclic GMP synthesis in these cells. Thus, only the agonists that are known to recognize the receptor's low-affinity conformation in order to elicit increases in cyclic GMP levels were capable of diminishing ligand binding. Taken together, our present results suggest that the receptor population that is sensitive to regulation by agonists includes both the pirenzepine high-affinity and the agonist low-affinity receptor binding states. In addition, the sensitivity of these receptor subsets to rapid regulation by agonists further implicates their involvement in desensitization of muscarinic receptor-mediated cyclic GMP formation.

  6. Induction of hepatic carbonyl reductase/20beta-hydroxysteroid dehydrogenase mRNA in rainbow trout downstream from sewage treatment works--possible roles of aryl hydrocarbon receptor agonists and oxidative stress.

    PubMed

    Albertsson, E; Larsson, D G J; Förlin, L

    2010-05-05

    Carbonyl reductase/20beta-hydroxysteroid dehydrogenase (CR/20beta-HSD) serves both as a key enzyme in the gonadal synthesis of maturing-inducing hormone in salmonids, and as an enzyme protecting against certain reactive oxygen species. We have previously shown that mRNA of the hepatic CR/20beta-HSD B isoform is increased in rainbow trout caged downstream from a Swedish sewage treatment plant. Here, we report an increase of both the A as well as B form in fish kept downstream from a second sewage treatment plant. The two mRNAs were also induced in fish hepatoma cells in vitro after exposure to effluent extract. This indicates that the effects observed in vivo could be a direct effect on the liver, i.e. the mRNA induction does not require a signal from any other organ. When fish were exposed in vivo to several effluents treated with more advanced methods (ozone, moving bed biofilm reactor or membrane bioreactor) the expression of hepatic mRNA CR/20beta-HSD A and B was significantly reduced. Their abundance did not parallel the reduction of estrogen-responsive transcripts, in agreement with our previous observations that ethinylestradiol is not a potent inducer. Treatment with norethisterone, methyltestosterone or hydrocortisone in vivo did not induce the hepatic CR/20beta-HSD A and B mRNA expression. In contrast, both isoforms were markedly induced by the aryl hydrocarbon receptor agonist beta-naphthoflavone as well as by the pro-oxidant herbicide paraquat. We hypothesize that the induction of CR/20beta-HSD A and B by sewage effluents could be due to anthropogenic contaminants stimulating the aryl hydrocarbon receptor and/or causing oxidative stress.

  7. Computational Study and Modified Design of Selective Dopamine D3 Receptor Agonists.

    PubMed

    Duan, Xinli; Zhang, Xin; Xu, Binglin; Wang, Fang; Lei, Ming

    2016-07-01

    Dopamine D3 receptor (D3 R) is considered as a potential target for the treatment of nervous system disorders, such as Parkinson's disease. Current research interests primarily focus on the discovery and design of potent D3 agonists. In this work, we selected 40 D3 R agonists as the research system. Comparative molecular field analysis (CoMFA) of three-dimensional quantitative structure-activity relationship (3D-QSAR), structure-selectivity relationship (3D-QSSR), and molecular docking was performed on D3 receptor agonists to obtain the details at atomic level. The results indicated that both the CoMFA model (r(2) = 0.982, q(2) = 0.503, rpred2 = 0.893, SEE  = 0.057, F = 166.308) for structure-activity and (r(2) = 0.876, q(2) = 0.436, rpred2 = 0.828, F = 52.645) for structure-selectivity have good predictive capabilities. Furthermore, docking studies on three compounds binding to D3 receptor were performed to analyze the binding modes and interactions. The results elucidate that agonists formed hydrogen bond and hydrophobic interactions with key residues. Finally, we designed six molecules under the guidance of 3D-QSAR/QSSR models. The activity and selectivity of designed molecules have been improved, and ADMET properties demonstrate they have low probability of hepatotoxicity (<0.5). These results from 3D-QSAR/QSSR and docking studies have great significance for designing novel dopamine D3 selective agonists in the future. © 2016 John Wiley & Sons A/S.

  8. A Cluster Headache Responsive to Ramelteon, a Selective Melatonin MT1/MT2 Receptor Agonist.

    PubMed

    Imai, Noboru

    2016-01-01

    Patients with cluster headaches occasionally fail to respond to conventional preventive treatments. We herein report a case of a patient with a cluster headache in which the symptoms were refractory to conventional preventive treatments except for high-dose glucocorticoids. The headache attacks occurred daily while sleeping, thus the patient suffered from insomnia. Ramelteon, a selective melatonin receptor agonist and a member of a new class of insomnia therapies, completely suppressed the attacks during sleep and provided rapid relief from insomnia. This is the first English case report to describe the efficacy of ramelteon as a preventive treatment for cluster headaches.

  9. Agonist photoaffinity label for the. beta. -adrenergic receptor

    SciTech Connect

    Resek, J.F.; Ruoho, A.E.

    1987-05-01

    An iodinated photosensitive derivative of norepinephrine, N-(p-azido-m-iodophenethylamidoisobutyryl)norepinephrine (NAIN), has been synthesized and characterized. Carrier-free radioiodinated NAIN ((/sup 125/I)-NAIN) was used at 1-2 x 10/sup -9/ M to photoaffinity label the ..beta..-adrenergic receptor in guinea pig lung membranes. SDS-PAGE analysis of (-)-alprenolol (10/sup -5/M) protectable (/sup 125/I)-NAIN labeling showed the same molecular weight polypeptide (65 kDa) that was specifically derivatized with the antagonist photolabel, (/sup 125/I)-IABP. Specific labeling of the ..beta..-adrenergic receptor with (/sup 125/I)-NAIN was dependent on the presence of MgCl/sub 2/ and the absence of guanyl nucleotide. GTP..gamma..S (10/sup -4/ M) abolished specific receptor labeling by (/sup 125/I)-NAIN. N-ethylmaleimide (2 mm) in the presence of (/sup 125/I)-NAIN protected against the guanyl nucleotide effect. These data are consistent with photolabeling by (/sup 125/I)-NAIN while the agonist, receptor, and GTP binding protein are in a high affinity complex.

  10. Therapeutic applications of TRAIL receptor agonists in cancer and beyond

    PubMed Central

    Amarante-Mendes, Gustavo P.; Griffith, Thomas S.

    2016-01-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings — ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  11. Disease Modification of Breast Cancer–Induced Bone Remodeling by Cannabinoid 2 Receptor Agonists

    PubMed Central

    Symons-Liguori, Ashley M; Largent-Milnes, Tally M; Havelin, Josh J; Ferland, Henry L; Chandramouli, Anupama; Owusu-Ankomah, Mabel; Nikolich-Zugich, Tijana; Bloom, Aaron P; Jimenez-Andrade, Juan Miguel; King, Tamara; Porreca, Frank; Nelson, Mark A; Mantyh, Patrick W; Vanderah, Todd W

    2015-01-01

    Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB2) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB2 agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB1/CB2 agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB2 agonists reduce breast cancer–induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB2 agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB2-mediated effects in vivo were reversed by concurrent treatment with a CB2 antagonist/inverse agonist but not with a CB1 antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB2 agonists as a

  12. A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent

    PubMed Central

    Oh, Eun Ju; Park, Jong Il; Lee, Ji Eun; Myung, Cheol Hwan; Kim, Su Yeon; Chang, Sung Eun; Hwang, Jae Sung

    2016-01-01

    BW723C86, a serotonin receptor 2B agonist, has been investigated as a potential therapeutic for various conditions such as anxiety, hyperphagia and hypertension. However, the functional role of BW723C86 against melanogenesis remains unclear. In this study, we investigate the effect of serotonin receptor 2B (5-HTR2B) agonist on melanogenesis and elucidate the mechanism involved. BW723C86 reduced melanin synthesis and intracellular tyrosinase activity in melan-A cells and normal human melanocytes. The expression of melanogenesis-related proteins (tyrosinase, TRP-1 and TRP-2) and microphthalmia-associated transcription factor (MITF) in melan-A cells decreased after BW723C86 treatment. The promoter activity of MITF was also reduced by BW723C86 treatment. The reduced level of MITF was associated with inhibition of protein kinase A (PKA) and cAMP response element-binding protein (CREB) activation by BW723C86 treatment. These results suggest that the serotonin agonist BW723C86 could be a potential therapeutic agent for skin hyperpigmentation disorders. PMID:27077852

  13. Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

    PubMed Central

    Taylor, Lewis; Christou, Ivy; Kapellos, Theodore S.; Buchan, Alice; Brodermann, Maximillian H.; Gianella-Borradori, Matteo; Russell, Angela; Iqbal, Asif J.; Greaves, David R.

    2015-01-01

    Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2-/- macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field. PMID:26033291

  14. Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor.

    PubMed

    Taylor, Lewis; Christou, Ivy; Kapellos, Theodore S; Buchan, Alice; Brodermann, Maximillian H; Gianella-Borradori, Matteo; Russell, Angela; Iqbal, Asif J; Greaves, David R

    2015-06-02

    Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2(-/-) macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field.

  15. Innovations in agonist maintenance treatment of opioid-dependent patients.

    PubMed

    Haasen, Christian; van den Brink, Wim

    2006-11-01

    To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid dependence. Findings show not only efficacy with respect to improvement of health, reduction of illicit drug use, reduction of criminality and stabilization of social conditions, but also cost effectiveness in the treatment of chronic treatment-resistant heroin addicts. Agonist maintenance treatment has become the first-line treatment for chronic opioid dependence. High-quality studies demonstrate the effectiveness of a growing number of different agonist maintenance treatments for opioid dependence such as methadone and buprenorphine. In addition, there is new evidence for the effectiveness of other agonists, mainly slow-release morphine, intravenous and inhalable diamorphine and possibly oral diamorphine. Maintenance treatment with intravenous or inhalable diamorphine should be implemented into the healthcare system to treat a group of severely dependent treatment-resistant patients. Furthermore, the opioid-dependent patients not under treatment need to be engaged in maintenance treatments through other harm reduction measures. Agonist maintenance treatment is very effective in stabilizing the health condition and social situation, while also reducing harm, thereby increasing life expectancy and quality of life.

  16. Fast Modulation of μ-Opioid Receptor (MOR) Recycling Is Mediated by Receptor Agonists*

    PubMed Central

    Roman-Vendrell, Cristina; Yu, Y. Joy; Yudowski, Guillermo Ariel

    2012-01-01

    The μ-opioid receptor (MOR) is a member of the G protein-coupled receptor family and the main target of endogenous opioid neuropeptides and morphine. Upon activation by ligands, MORs are rapidly internalized via clathrin-coated pits in heterologous cells and dissociated striatal neurons. After initial endocytosis, resensitized receptors recycle back to the cell surface by vesicular delivery for subsequent cycles of activation. MOR trafficking has been linked to opioid tolerance after acute exposure to agonist, but it is also involved in the resensitization process. Several studies describe the regulation and mechanism of MOR endocytosis, but little is known about the recycling of resensitized receptors to the cell surface. To study this process, we induced internalization of MOR with [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) and morphine and imaged in real time single vesicles recycling receptors to the cell surface. We determined single vesicle recycling kinetics and the number of receptors contained in them. Then we demonstrated that rapid vesicular delivery of recycling MORs to the cell surface was mediated by the actin-microtubule cytoskeleton. Recycling was also dependent on Rab4, Rab11, and the Ca2+-sensitive motor protein myosin Vb. Finally, we showed that recycling is acutely modulated by the presence of agonists and the levels of cAMP. Our work identifies a novel trafficking mechanism that increases the number of cell surface MORs during acute agonist exposure, effectively reducing the development of opioid tolerance. PMID:22378794

  17. Fast modulation of μ-opioid receptor (MOR) recycling is mediated by receptor agonists.

    PubMed

    Roman-Vendrell, Cristina; Yu, Y Joy; Yudowski, Guillermo Ariel

    2012-04-27

    The μ-opioid receptor (MOR) is a member of the G protein-coupled receptor family and the main target of endogenous opioid neuropeptides and morphine. Upon activation by ligands, MORs are rapidly internalized via clathrin-coated pits in heterologous cells and dissociated striatal neurons. After initial endocytosis, resensitized receptors recycle back to the cell surface by vesicular delivery for subsequent cycles of activation. MOR trafficking has been linked to opioid tolerance after acute exposure to agonist, but it is also involved in the resensitization process. Several studies describe the regulation and mechanism of MOR endocytosis, but little is known about the recycling of resensitized receptors to the cell surface. To study this process, we induced internalization of MOR with [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) and morphine and imaged in real time single vesicles recycling receptors to the cell surface. We determined single vesicle recycling kinetics and the number of receptors contained in them. Then we demonstrated that rapid vesicular delivery of recycling MORs to the cell surface was mediated by the actin-microtubule cytoskeleton. Recycling was also dependent on Rab4, Rab11, and the Ca(2+)-sensitive motor protein myosin Vb. Finally, we showed that recycling is acutely modulated by the presence of agonists and the levels of cAMP. Our work identifies a novel trafficking mechanism that increases the number of cell surface MORs during acute agonist exposure, effectively reducing the development of opioid tolerance.

  18. Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.

    PubMed

    Ryabtsova, Oksana; Joossens, Jurgen; Van Der Veken, Pieter; Vanden Berghe, Wim; Augustyns, Koen; De Winter, Hans

    2016-10-15

    The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.

  19. Biased signaling by peptide agonists of protease activated receptor 2.

    PubMed

    Jiang, Yuhong; Yau, Mei-Kwan; Kok, W Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A; Suen, Jacky Y; Fairlie, David P

    2017-02-07

    Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.

  20. Thiazolidinediones are Partial Agonists for the Glucocorticoid Receptor

    PubMed Central

    Matthews, L; Berry, A; Tersigni, M; D’Acquisto, F; Ianaro, A; Ray, D

    2014-01-01

    Although thiazolidinediones were designed as specific PPARγ-ligands there is evidence for some off-target effects mediated by a non-PPARγ mechanism. Previously we have shown that Rosiglitazone has anti-inflammatory actions not explicable by activation of PPARγ, but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-GFP, and endogenous GR in HeLa and U20S cells but with slower kinetics than Dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding specific effect. Rosiglitazone drives luciferase expression from a simple GRE containing reporter gene in a GR-dependent manner (EC50 4μM), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits Dexamethasone driven reporter gene activity (IC50 2.9μM) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPARγ-null cells suggesting both GR-dependence and PPARγ-independence. Rosiglitazone also activates a GAL4-GR chimera, driving a UAS promoter, demonstrating DNA template sequence independence, and furthermore enhanced SRC1-GR interaction, measured by a mammalian two-hybrid assay. Both Ciglitazone and Pioglitazone, structurally related to Rosiglitazone, show similar effects on the GR. The antiproliferative effect of Rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of Rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the anti-diabetic actions of Rosiglitazone. PMID:18801908

  1. Effects of 5-HT4 receptor agonists and antagonists in learning.

    PubMed

    Meneses, A; Hong, E

    1997-03-01

    In the present work, the effects of pre- or post-training (ip) injection of BIMU1 and BIMU8 (5-HT4 agonists) were figured out in the autoshaping learning task. Furthermore, the post-training effects of these agonists after treatment with SDZ 205-557 and GR 125487D (5-HT4 antagonists) or p-Chloroamphetamine (PCA) were also explored. Animals were individually trained in a lever-press response on the autoshaping task and 24 hours later were tested. The results showed that pre-training injection of BIMU1 (5 20 mg/Kg) or BIMU8 (20 mg/Kg) increased the CR; in contrast, the post-training administration of BIMU1 (10-20 mg/Kg) or BIMU8 (5 and 20 mg/Kg) decreased it. Further experiments revealed that the post-training injections of SDZ 205-557 (1.0-10.0 mg/Kg) or GR 125487D (0.39-1.56 mg/Kg) by themselves did not alter the CR. When BIMU1 or BIMU8 was administered to rats pretreated with SDZ 205-557 (10 mg/Kg) or GR 125487D (0.78 mg/Kg), the decrement induced by 5-HT4 the agonists was reversed; in contrast, the administration of PCA failed to modify the CR or the agonist-induced responses. The findings showed that the pre-training stimulation of 5-HT4 receptors enhanced the acquisition of CR, while, post-training activation of 5-HT4 receptors, impaired the consolidation of learning. The latter effect was not altered by PCA pretreatment. The data show that 5-HT4 receptors are involved in the acquisition and consolidation of learning. It seems that postsynaptic 5-HT4 receptors are involved in the latter effect.

  2. CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy.

    PubMed

    Murad, Yanal M; Clay, Timothy M; Lyerly, H Kim; Morse, Michael A

    2007-08-01

    Stimulation of toll-like receptor (TLR)9 activates human plasmacytoid dendritic cells and B cells, and induces potent innate immune responses in preclinical tumor models and in patients. CpG oligodeoxynucleotides (ODNs) are TLR9 agonists that show promising results as vaccine adjuvants and in the treatment of cancers, infections, asthma and allergy. PF-3512676 (ProMune) was developed as a TLR9 agonist for the treatment of cancer as monotherapy and as an adjuvant in combination with chemo- and immunotherapy. Phase I and II trials have tested this drug in several hematopoietic and solid tumors. Pfizer has initiated Phase III trials to test PF-3512676 in combination with standard chemotherapy for non-small-cell lung cancer.

  3. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,4)-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter (3H)SR 95531 (2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter (3H)Ro15-4513 or (3H)flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.

  4. Trial Watch: Toll-like receptor agonists in oncological indications.

    PubMed

    Aranda, Fernando; Vacchelli, Erika; Obrist, Florine; Eggermont, Alexander; Galon, Jérôme; Sautès-Fridman, Catherine; Cremer, Isabelle; Henrik Ter Meulen, Jan; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.

  5. Muscarinic Receptor Agonists and Antagonists: Effects on Cancer

    PubMed Central

    2012-01-01

    Many epithelial and endothelial cells express a cholinergic autocrine loop in which acetylcholine acts as a growth factor to stimulate cell growth. Cancers derived from these tissues similarly express a cholinergic autocrine loop and ACh secreted by the cancer or neighboring cells interacts with M3 muscarinic receptors expressed on the cancer cells to stimulate tumor growth. Primary proliferative pathways involve MAPK and Akt activation. The ability of muscarinic agonists to stimulate, and M3 antagonists to inhibit tumor growth has clearly been demonstrated for lung and colon cancer. The ability of muscarinic agonists to stimulate growth has been shown for melanoma, pancreatic, breast, ovarian, prostate and brain cancers, suggesting that M3 antagonists will also inhibit growth of these tumors as well. As yet no clinical trials have proven the efficacy of M3 antagonists as cancer therapeutics, though the widespread clinical use and low toxicity of M3 antagonists support the potential role of these drugs as adjuvants to current cancer therapies. PMID:22222710

  6. Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice

    PubMed Central

    Allen, Amy E. Clipperton; Cragg, Cheryl L.; Wood, Alexis J.; Pfaff, Donald W.; Choleris, Elena

    2010-01-01

    Summary Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ERα) or beta (ERβ) knockout (KO) mice show that long-term inactivation of ERα decreases, while inactivation of ERβ increases, male aggression. Opposite effects were found in female αERKO and βERKO mice. The role of acute activation of ERα or ERβ in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ERβ selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15 min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: 1) effects of WAY-200070 on each sex and gonadal condition; 2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice WAY-200070 increased agonistic behaviors such as pushing down and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ERβ mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ERβ in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ERβ. Thus, acute activation of ERβ similarly mediates agonistic behavior in adult male and female CD-1 mice. PMID:20129736

  7. Anti-fibrotic Potential of AT2 Receptor Agonists

    PubMed Central

    Wang, Yan; Del Borgo, Mark; Lee, Huey W.; Baraldi, Dhaniel; Hirmiz, Baydaa; Gaspari, Tracey A.; Denton, Kate M.; Aguilar, Marie-Isabel; Samuel, Chrishan S.; Widdop, Robert E.

    2017-01-01

    There are a number of therapeutic targets to treat organ fibrosis that are under investigation in preclinical models. There is increasing evidence that stimulation of the angiotensin II type 2 receptor (AT2R) is a novel anti-fibrotic strategy and we have reviewed the published in vivo preclinical data relating to the effects of compound 21 (C21), which is the only nonpeptide AT2R agonist that is currently available for use in chronic preclinical studies. In particular, the differential influence of AT2R on extracellular matrix status in various preclinical fibrotic models is discussed. Collectively, these studies demonstrate that pharmacological AT2R stimulation using C21 decreases organ fibrosis, which has been most studied in the setting of cardiovascular and renal disease. In addition, AT2R-mediated anti-inflammatory effects may contribute to the beneficial AT2R-mediated anti-fibrotic effects seen in preclinical models. PMID:28912715

  8. Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists.

    PubMed

    Mays, Suzanne G; Okafor, C Denise; Whitby, Richard J; Goswami, Devrishi; Stec, Józef; Flynn, Autumn R; Dugan, Michael C; Jui, Nathan T; Griffin, Patrick R; Ortlund, Eric A

    2016-12-02

    Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. Although preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth nor do they expand the pocket like phospholipids. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable face-to-face π-π-stacking with the LRH-1 residue His-390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Differential role of protein kinase C in desensitization of muscarinic receptor induced by phorbol esters and receptor agonists

    SciTech Connect

    Lai, Wi Sheung.

    1989-01-01

    PKC, a phorbol ester receptor, copurified with specific binding sites of ({sup 3}H)phorbol-12,13,-dibutyrate (({sup 3}H)PDBu). The specific binding of ({sup 3}H)PDBu to intact cells was saturable to a single class of binding sites. The PKC and phorbol ester receptors in N1E-115 cells can be down regulated by prolonged phorbol ester incubation. Phorbol 12-myristate 13-acetate (PMA) suppressed muscarinic receptor-mediated cyclic GMP response in a time-dependent and a concentration-dependent fashion and the suppressive effect of PMA could be attenuated by a protein kinase inhibitor, H-7, as well as by down-regulation of the PKC through long-term incubation with PDBu. Exposure of the cells to the muscarinic agonist carbamylcholine also desensitized subsequent CBC-mediated cyclic GMP response. However, pretreatment with carbamylcholine did not desensitize histamine-induced cyclic GMP formation while treatment with PMA suppressed this histamine-mediated response. Preincubation of the cells with CBC, but not with phorbol ester, resulted in down-regulation of muscarinic receptors. The loss of muscarinic receptors induced by agonist even occurred when the phosphoinositide hydrolysis response was suppressed.

  10. Recent advances in the development of farnesoid X receptor agonists

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  11. PPAR Agonists for the Prevention and Treatment of Lung Cancer

    PubMed Central

    Banno, Asoka

    2017-01-01

    Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARβ/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARβ/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease. PMID:28316613

  12. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes.

    PubMed

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan

    2015-07-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.

  13. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    SciTech Connect

    Raufman, Jean-Pierre; Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre-treatment

  14. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method.

    PubMed

    Hämmig, Robert; Kemter, Antje; Strasser, Johannes; von Bardeleben, Ulrich; Gugger, Barbara; Walter, Marc; Dürsteler, Kenneth M; Vogel, Marc

    2016-01-01

    Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use. We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms. Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction.

  15. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method

    PubMed Central

    Hämmig, Robert; Kemter, Antje; Strasser, Johannes; von Bardeleben, Ulrich; Gugger, Barbara; Walter, Marc; Dürsteler, Kenneth M; Vogel, Marc

    2016-01-01

    Background Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use. Cases We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms. Discussion Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction. PMID:27499655

  16. Uterine fibroid shrinkage after short-term use of selective progesterone receptor modulator or gonadotropin-releasing hormone agonist

    PubMed Central

    Lee, Min Jin; Seong, Seok Ju; Kim, Mi-La; Jung, Yong Wook; Kim, Mi Kyoung; Bae, Hyo Sook; Kim, Da Hee; Hwang, Ji Young

    2017-01-01

    Objective The aim of this study was to evaluate the effect of short-term use of selective progesterone receptor modulator (SPRM) or gonadotropin-releasing hormone (GnRH) agonist on uterine fibroid shrinkage among Korean women. Methods This retrospective study involved 101 women with symptomatic uterine fibroids who received ulipristal acetate (SPRM, n=51) and leuprolide acetate (GnRH agonist, n=50) for 3 months between November 2013 and February 2015. The fibroid volume was measured both before and after treatment using ultrasonography, computed tomography, and magnetic resonance imaging. The outcomes were compared between the SPRM and GnRH agonist groups. Results The median rate of fibroid volume reduction after SPRM treatment was 12.4% (IQR −14.5% to 40.5%) which was significantly lower than the reduction rate observed after GnRH agonist treatment (median 34.9%, IQR 14.7% to 48.6%, P=0.004). 19 of 51 (37.3%) patients with SPRM treatment did not show any response of volume shrinkage, while 7 of 50 (14.0%) women with GnRH agonist showed no response (P=0.007). Conclusion Short-term SPRM treatment yields lower volume reduction than GnRH agonist treatment in Korean women with symptomatic fibroids. Further large-scale randomized trials are needed to confirm our findings. PMID:28217674

  17. Uterine fibroid shrinkage after short-term use of selective progesterone receptor modulator or gonadotropin-releasing hormone agonist.

    PubMed

    Lee, Min Jin; Yun, Bo Seong; Seong, Seok Ju; Kim, Mi-La; Jung, Yong Wook; Kim, Mi Kyoung; Bae, Hyo Sook; Kim, Da Hee; Hwang, Ji Young

    2017-01-01

    The aim of this study was to evaluate the effect of short-term use of selective progesterone receptor modulator (SPRM) or gonadotropin-releasing hormone (GnRH) agonist on uterine fibroid shrinkage among Korean women. This retrospective study involved 101 women with symptomatic uterine fibroids who received ulipristal acetate (SPRM, n=51) and leuprolide acetate (GnRH agonist, n=50) for 3 months between November 2013 and February 2015. The fibroid volume was measured both before and after treatment using ultrasonography, computed tomography, and magnetic resonance imaging. The outcomes were compared between the SPRM and GnRH agonist groups. The median rate of fibroid volume reduction after SPRM treatment was 12.4% (IQR -14.5% to 40.5%) which was significantly lower than the reduction rate observed after GnRH agonist treatment (median 34.9%, IQR 14.7% to 48.6%, P=0.004). 19 of 51 (37.3%) patients with SPRM treatment did not show any response of volume shrinkage, while 7 of 50 (14.0%) women with GnRH agonist showed no response (P=0.007). Short-term SPRM treatment yields lower volume reduction than GnRH agonist treatment in Korean women with symptomatic fibroids. Further large-scale randomized trials are needed to confirm our findings.

  18. Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors.

    PubMed

    Koch, Thomas; Wu, Dai-Fei; Yang, Li-Quan; Brandenburg, Lars-Ove; Höllt, Volker

    2006-04-01

    We have recently shown that the mu-opioid receptor [MOR1, also termed mu-opioid peptide (MOP) receptor] is associated with the phospholipase D2 (PLD2), a phospholipid-specific phosphodiesterase located in the plasma membrane. We further demonstrated that, in human embryonic kidney (HEK) 293 cells co-expressing MOR1 and PLD2, treatment with (D-Ala2, Me Phe4, Glyol5)enkephalin (DAMGO) led to an increase in PLD2 activity and an induction of receptor endocytosis, whereas morphine, which does not induce opioid receptor endocytosis, failed to activate PLD2. In contrast, a C-terminal splice variant of the mu-opioid receptor (MOR1D, also termed MOP(1D)) exhibited robust endocytosis in response to both DAMGO and morphine treatment. We report here that MOR1D also mediates an agonist-independent (constitutive) PLD2-activation facilitating agonist-induced and constitutive receptor endocytosis. Inhibition of PLD2 activity by over-expression of a dominant negative PLD2 (nPLD2) blocked the constitutive PLD2 activation and impaired the endocytosis of MOR1D receptors. Moreover, we provide evidence that the endocytotic trafficking of the delta-opioid receptor [DOR, also termed delta-opioid peptide (DOP) receptor] and cannabinoid receptor isoform 1 (CB1) is also mediated by a PLD2-dependent pathway. These data indicate the generally important role for PLD2 in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor (GPCR) endocytosis.

  19. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations.

    PubMed

    Carris, Nicholas W; Taylor, James R; Gums, John G

    2014-12-01

    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  20. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics.

  1. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    PubMed

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  2. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    PubMed Central

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  3. Identification of a naturally occurring retinoid X receptor agonist from Brazilian green propolis.

    PubMed

    Nakashima, Ken-Ichi; Murakami, Tohru; Tanabe, Hiroki; Inoue, Makoto

    2014-10-01

    Brazilian green propolis (BGP), a resinous substance produced from Baccharis dracunculifolia by Africanized honey bees (Apis mellifera), is used as a folk medicine. Our present study explores the retinoid X receptor (RXR) agonistic activity of BGP and the identification of an RXR agonist in its extract. RXRα agonistic activity was evaluated using a luciferase reporter gene assay. Isolation of the RXRα agonist from the ethanolic extract of BGP was performed using successive silica gel and a reversed phase column chromatography. The interaction between the isolated RXRα agonist and RXRα protein was predicted by a receptor-ligand docking simulation. The nuclear receptor (NR) cofactor assay was used to estimate whether the isolated RXRα agonist bound to various NRs, including RXRs and peroxisome proliferator-activated receptors (PPARs). We further examined its effect on adipogenesis in 3T3-L1 fibroblasts. We identified drupanin as an RXRα agonist with an EC50 value of 4.8 ± 1.0 μM. Drupanin activated three RXR subtypes by a similar amount and activated PPARγ moderately. Additionally, drupanin induced adipogenesis and elevated aP2 mRNA levels in 3T3-L1 fibroblasts. Drupanin, a component of BGP, is a novel RXR agonist with slight PPARγ agonistic activity. This study revealed for the first time that BGP activates RXR and drupanin is an RXR agonist in its extract. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Preclinical Evidence That 5-HT1B Receptor Agonists Show Promise as Medications for Psychostimulant Use Disorders.

    PubMed

    Garcia, Raul; Cotter, Austin R; Leslie, Kenneth; Olive, M Foster; Neisewander, Janet L

    2017-08-01

    5-HT1B receptor agonists enhance cocaine intake during daily self-administration sessions but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1B receptor agonists produce similar abstinence-dependent effects on methamphetamine intake. Male rats were trained to self-administer methamphetamine (0.1 mg/kg, i.v.) on low (fixed ratio 5 and variable ratio 5) and high (progressive ratio) effort schedules of reinforcement until intake was stable. Rats were then tested for the effects of the selective 5-HT1B receptor agonist, CP 94,253 (5.6 or 10 mg/kg), or the less selective but clinically available 5-HT1B/1D receptor agonist, zolmitriptan (10 mg/kg), on methamphetamine self-administration both before and after a 21-day forced abstinence period during which the rats remained in their home cages. The inverted U-shaped, methamphetamine dose-response function for intake on the fixed ratio 5 schedule was shifted downward by CP 94,253 both before and after abstinence. The CP 94,253-induced decrease in methamphetamine intake was replicated in rats tested on a variable ratio 5 schedule, and the 5-HT1B receptor antagonist SB 224,289 (10 mg/kg) reversed this effect. CP 94,253 also attenuated methamphetamine intake on a progressive ratio schedule both pre- and postabstinence. Similarly, zolmitriptan attenuated methamphetamine intake on a variable ratio 5 schedule both pre- and postabstinence, and the latter effect was sustained after each of 2 more treatments given every 2 to 3 days prior to daily sessions. Unlike the abstinence-dependent effect of 5-HT1B receptor agonists on cocaine intake reported previously, both CP 94,253 and zolmitriptan decreased methamphetamine intake regardless of abstinence. These findings suggest that 5-HT1B receptor agonists may have clinical efficacy for psychostimulant use disorders.

  5. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time

    PubMed Central

    Guo, Dong; Mulder-Krieger, Thea; IJzerman, Adriaan P; Heitman, Laura H

    2012-01-01

    BACKGROUND AND PURPOSE The adenosine A2A receptor belongs to the superfamily of GPCRs and is a promising therapeutic target. Traditionally, the discovery of novel agents for the A2A receptor has been guided by their affinity for the receptor. This parameter is determined under equilibrium conditions, largely ignoring the kinetic aspects of the ligand-receptor interaction. The aim of this study was to assess the binding kinetics of A2A receptor agonists and explore a possible relationship with their functional efficacy. EXPERIMENTAL APPROACH We set up, validated and optimized a kinetic radioligand binding assay (a so-called competition association assay) at the A2A receptor from which the binding kinetics of unlabelled ligands were determined. Subsequently, functional efficacies of A2A receptor agonists were determined in two different assays: a novel label-free impedance-based assay and a more traditional cAMP determination. KEY RESULTS A simplified competition association assay yielded an accurate determination of the association and dissociation rates of unlabelled A2A receptor ligands at their receptor. A correlation was observed between the receptor residence time of A2A receptor agonists and their intrinsic efficacies in both functional assays. The affinity of A2A receptor agonists was not correlated to their functional efficacy. CONCLUSIONS AND IMPLICATIONS This study indicates that the molecular basis of different agonist efficacies at the A2A receptor lies within their different residence times at this receptor. PMID:22324512

  6. Toll receptor agonist therapy of skin cancer and cutaneous T-cell lymphoma.

    PubMed

    Huen, Auris O; Rook, Alain H

    2014-03-01

    The use of agents which exhibit the ability to potently activate the innate immune response has gained significant interest as therapeutics to treat cancer. We will review the history and the current applications of these agents to treat skin cancer and cutaneous T-cell lymphoma. Particular attention has been focused upon Toll-like receptor (TLR) agonists, including imidazoquinolines, which can trigger TLR 7 and TLR 8, and cytosine-phosphate-guanine (CpG) oligodeoxynucleotides, which activate TLR 9-expressing cells. Imiquimod, a TLR 7 agonist, has been found to be efficacious for basal cell and squamous cell cancers, as well as cutaneous T-cell lymphoma and lentigo maligna melanoma. CpGs have demonstrated efficacy for cutaneous T-cell lymphoma. Additional more potent compounds, including resiquimod, are presently in clinical trials for several types of skin cancers. TLR agonists that can activate the innate immune response have been used to treat a variety of skin cancers including basal cell cancer, squamous cell cancer, lentigo maligna melanoma and cutaneous T-cell lymphoma. Significant clinical efficacy has been observed for all of these conditions. It is anticipated that additional members of the TLR agonist family will be available in the clinic for the future treatment of skin cancers as well as other malignancies.

  7. Platelet-activating factor receptor agonists mediate xeroderma pigmentosum A photosensitivity.

    PubMed

    Yao, Yongxue; Harrison, Kathleen A; Al-Hassani, Mohammed; Murphy, Robert C; Rezania, Samin; Konger, Raymond L; Travers, Jeffrey B

    2012-03-16

    To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa-/-) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-α production in Xpa-/- mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity.

  8. Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity*

    PubMed Central

    Yao, Yongxue; Harrison, Kathleen A.; Al-Hassani, Mohammed; Murphy, Robert C.; Rezania, Samin; Konger, Raymond L.; Travers, Jeffrey B.

    2012-01-01

    To date, oxidized glycerophosphocholines (Ox-GPCs) with platelet-activating factor (PAF) activity produced non-enzymatically have not been definitively demonstrated to mediate any known disease processes. Here we provide evidence that these Ox-GPCs play a pivotal role in the photosensitivity associated with the deficiency of the DNA repair protein xeroderma pigmentosum type A (XPA). It should be noted that XPA-deficient cells are known to have decreased antioxidant defenses. These studies demonstrate that treatment of human XPA-deficient fibroblasts with the pro-oxidative stressor ultraviolet B (UVB) radiation resulted in increased reactive oxygen species and PAF receptor (PAF-R) agonistic activity in comparison with gene-corrected cells. The UVB irradiation-generated PAF-R agonists were inhibited by antioxidants. UVB irradiation of XPA-deficient (Xpa−/−) mice also resulted in increased PAF-R agonistic activity and skin inflammation in comparison with control mice. The increased UVB irradiation-mediated skin inflammation and TNF-α production in Xpa−/− mice were blocked by systemic antioxidants and by PAF-R antagonists. Structural characterization of PAF-R-stimulating activity in UVB-irradiated XPA-deficient fibroblasts using mass spectrometry revealed increased levels of sn-2 short-chain Ox-GPCs along with native PAF. These studies support a critical role for PAF-R agonistic Ox-GPCs in the pathophysiology of XPA photosensitivity. PMID:22303003

  9. Agonist-induced internalization and desensitization of the apelin receptor.

    PubMed

    Pope, George R; Tilve, Sharada; McArdle, Craig A; Lolait, Stephen J; O'Carroll, Anne-Marie

    2016-12-05

    Apelin acts via the G protein-coupled apelin receptor (APJ) to mediate effects on cardiovascular and fluid homeostasis. G protein-coupled receptor (GPCR) trafficking has an important role in the regulation of receptor signalling pathways and cellular functions, however in the case of APJ the mechanisms and proteins involved in apelin-induced trafficking are not well understood. We generated a stable HEK-293 cell line expressing N-terminus HA-tagged mouse (m) APJ, and used a semi-automated imaging protocol to quantitate APJ trafficking and ERK1/2 activation following stimulation with [Pyr(1)]apelin-13. The mechanisms of [Pyr(1)]apelin-13-induced internalization and desensitization were explored using dominant-negative mutant (DNM) cDNA constructs of G protein-coupled receptor kinase 2 (GRK2), β-arrestin1, EPS15 and dynamin. The di-phosphorylated ERK1/2 (ppERK1/2) response to [Pyr(1)]apelin-13 desensitized during sustained stimulation, due to upstream APJ-specific adaptive changes. Furthermore, [Pyr(1)]apelin-13 stimulation caused internalization of mAPJ via clathrin coated vesicles (CCVs) and also caused a rapid reduction in cell surface and whole cell HA-mAPJ. Our data suggest that upon continuous agonist exposure GRK2-mediated phosphorylation targets APJ to CCVs that are internalized from the cell surface in a β-arrestin1-independent, EPS15- and dynamin-dependent manner. Internalization does not appear to contribute to the desensitization of APJ-mediated ppERK1/2 activation in these cells. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  10. Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

    PubMed Central

    Gupta, Achla; Gomes, Ivone; Bobeck, Erin N.; Fakira, Amanda K.; Massaro, Nicholas P.; Sharma, Indrajeet; Cavé, Adrien; Hamm, Heidi E.; Parello, Joseph

    2016-01-01

    Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10- to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non–histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects. PMID:27162327

  11. Identification of a Novel Non-retinoid Pan Inverse Agonist of the Retinoic Acid Receptors

    PubMed Central

    Busby, Scott A.; Kumar, Naresh; Kuruvilla, Dana S.; Istrate, Monica A.; Conkright, Juliana J.; Wang, Yongjun; Kamenecka, Theodore M.; Cameron, Michael D.; Roush, William R.; Burris, Thomas P.; Griffin, Patrick R.

    2011-01-01

    Retinoids are potent forms of vitamin A and are involved in a broad range of physiological processes and the pharmacological effects of retinoids are primarily mediated by the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Several natural and synthetic RAR modulators have proven to be clinically useful for a number of therapeutic indications including cancer, psoriasis, and diabetes. Unfortunately, these agents lead to a number of significant side effects. Most synthetic retinoid ligands are based on the retinoid scaffold and thus have similarities to the natural ligand with all previously disclosed RAR ligands having a carboxylic acid that makes a critical ionic bridge within the ligand binding domain of the receptors. The potential therapeutic value offered from RAR modulation provides the impetus to identify novel ligands based on unique scaffolds that may offer improved toxicity and pharmacokinetic profiles. Here we describe the identification of an atypical RAR inverse agonist that represents the first non-acid, non-retinoid direct modulator of RAR receptor subfamily. SR-0065 functions as a pan-RAR inverse agonist suppressing the basal activity of RARα, RARβ, and RARγ as well as inhibiting agonist induced RAR activity. SR-0065 treatment enhanced receptor interaction with a peptide representative of the corepressor SMRT and in cells SR-0065 enhances recruitment of SMRT to RARγ. The acid form of SR-0065, SR-1758, was inactive in all assays. Thus, SR-0065 represents a new class of non-acid, non-retinoid RAR modulator that may be used as a point to initiate development of improved RAR-targeted drugs. PMID:21381756

  12. Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases.

    PubMed

    Wallukat, Gerd; Schimke, Ingolf

    2014-05-01

    Agonistic autoantibodies (AABs) against G-protein-coupled receptor (GPCR) are present mainly in diseases of the cardiovascular system or in diseases associated with cardiovascular disturbances. The increasing knowledge about the role of autoantibodies against G-protein-coupled receptor (GPCR-AABs) as pathogenic drivers, the resulting development of strategies aimed at their removal or neutralization, and the evidenced patient benefit associated with such therapies have created the need for a summary of GPCR-AAB-associated diseases. Here, we summarize the present knowledge about GPCR-AABs in cardiovascular diseases. The identity of the GPCR-AABs and their prevalence in each of several specific cardiovascular diseases are documented. The structure of GPCR is also briefly discussed. Using this information, differences between classic agonists and GPCR-AABs in their GPCR binding and activation are presented and the resulting pathogenic consequences are discussed. Furthermore, treatment strategies that are currently under study, most of which are aimed at the removal and in vivo neutralization of GPCR-AABs, are indicated and their patient benefits discussed. In this context, immunoadsorption using peptides/proteins or aptamers as binders are introduced. The use of peptides or aptamers for in vivo neutralization of GPCR-AABs is also described. Particular attention is given to the GPCR-AABs directed against the adrenergic beta1-, beta2-, and α1-receptor as well as the muscarinic receptor M2, angiotensin II-angiotensin receptor type I, endothelin1 receptor type A, angiotensin (1-7) Mas-receptor, and 5-hydroxytryptamine receptor 4. Among the diseases associated with GPCR-AABs, special focus is given to idiopathic dilated cardiomyopathy, Chagas' cardiomyopathy, malignant and pulmonary hypertension, and kidney diseases. Relationships of GPCR-AABs are indicated to glaucoma, peripartum cardiomyopathy, myocarditis, pericarditis, preeclampsia, Alzheimer's disease, Sj

  13. A novel treatment of global cerebral ischaemia with a glycine partial agonist.

    PubMed

    Von Lubitz, D K; Lin, R C; McKenzie, R J; Devlin, T M; McCabe, R T; Skolnick, P

    1992-08-14

    Chronic treatment of gerbils with 1-aminocyclopropanecarboxylic acid (a high affinity, partial agonist at strychnine-insensitive glycine receptors) resulted in a 3-fold increase in survival, a significant improvement in neurological status, and an extensive protection of vulnerable brain regions following severe forebrain ischaemia. A bolus of 1-aminocyclopropanecarboxylic acid 30 min prior to ischaemia did not further improve outcome compared to gerbils receiving their last injection 24 h prior to ischaemia. These findings are consistent with the hypothesis that chronic treatment with a glycine partial agonist desensitizes the N-methyl-D-aspartate receptor complex. Pharmacological intervention at the strychnine-insensitive glycine receptor may be an effective means of ameliorating the consequences of neuronal degeneration caused by excitotoxic phenomena.

  14. Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells

    PubMed Central

    Shen, Minqian; Shi, Haifei

    2016-01-01

    Obesity is a significant risk factor for certain cancers, including hepatocellular carcinoma (HCC). Leptin, a hormone secreted by white adipose tissue, precipitates HCC development. Epidemiology data show that men have a much higher incidence of HCC than women, suggesting that estrogens and its receptors may inhibit HCC development and progression. Whether estrogens antagonize oncogenic action of leptin is uncertain. To investigate potential inhibitory effects of estrogens on leptin-induced HCC development, HCC cell line HepG2 cells were treated with leptin in combination with 17 β-estradiol (E2), estrogen receptor-α (ER-α) selective agonist PPT, ER-β selective agonist DPN, or G protein-coupled ER (GPER) selective agonist G-1. Cell number, proliferation, and apoptosis were determined, and leptin- and estrogen-related intracellular signaling pathways were analyzed. HepG2 cells expressed a low level of ER-β mRNA, and leptin treatment increased ER-β expression. E2 suppressed leptin-induced HepG2 cell proliferation and promoted cell apoptosis in a dose-dependent manner. Additionally E2 reversed leptin-induced STAT3 and leptin-suppressed SOCS3, which was mainly achieved by activation of ER-β. E2 also enhanced ERK via activating ER-α and GPER and activated p38/MAPK via activating ER-β. To conclude, E2 and its receptors antagonize the oncogenic actions of leptin in HepG2 cells by inhibiting cell proliferation and stimulating cell apoptosis, which was associated with reversing leptin-induced changes in SOCS3/STAT3 and increasing p38/MAPK by activating ER-β, and increasing ERK by activating ER-α and GPER. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatment for HCC patients. PMID:26982332

  15. Beyond glucose lowering: glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system.

    PubMed

    Vergès, B; Bonnard, C; Renard, E

    2011-12-01

    Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family: in the presence of elevated blood glucose, it stimulates insulin secretion and inhibits glucagon production. In addition, GLP-1 slows gastric emptying. GLP-1 secretion has also been reported to potentially affect patients with type 2 diabetes (T2DM) compared with non-diabetics and, as enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4) shortens the GLP-1 half-life to a few minutes, GLP-1 receptor agonists such as exenatide twice daily (BID) and liraglutide have been developed, and have become part of the management of patients with T2DM. This review focuses on the potential beneficial effects of these compounds beyond those associated with improvements in blood glucose control and weight loss, including changes in the cardiovascular and central nervous systems. This was a state-of-the-art review of the literature to evaluate the relationships between GLP-1, GLP-1 receptor agonists, weight and the cardiovascular system. GLP-1 receptor agonists improve glucose control and do not significantly increase the risk of hypoglycaemia. Also, this new class of antidiabetic drugs was shown to favour weight loss. Mechanisms may involve central action, direct action by reduction of food intake and probably indirect action through slowing of gastric emptying. The relative importance of each activity remains unclear. Weight loss may improve cardiovascular outcomes in patients with T2DM, although GLP-1 receptor agonists may have other direct and indirect effects on the cardiovascular system. Reductions in myocardial infarct size and improvements in cardiac function have been seen in animal models. Beneficial changes in cardiac function were also demonstrated in patients with myocardial infarcts or heart failure. Indirect effects could involve a reduction in blood pressure and potential effects on oxidation. However, the mechanisms involved in the pleiotropic effects of GLP-1 receptor agonists have yet to

  16. Impact of GLP-1 Receptor Agonists on Major Gastrointestinal Disorders for Type 2 Diabetes Mellitus: A Mixed Treatment Comparison Meta-Analysis

    PubMed Central

    Sun, Feng; Yu, Kai; Yang, Zhirong; Wu, Shanshan; Zhang, Yuan; Shi, Luwen; Ji, Linong; Zhan, Siyan

    2012-01-01

    Aim. We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM). Methods. RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed. Results. All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed. Conclusions. Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance. PMID:23365557

  17. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    SciTech Connect

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  18. PPAR δ agonist GW0742 interacts weakly with multiple nuclear receptors including the vitamin D receptor

    PubMed Central

    Nandhikonda, Premchendar; Yasgar, Adam; Baranowski, Athena M.; Sidhu, Preetpal S.; McCallum, Megan M.; Pawlak, Alan J.; Teske, Kelly; Feleke, Belaynesh; Yuan, Nina Y.; Kevin, Chinedum; Bikle, Daniel D.; Ayers, Steven D.; Webb, Paul; Rai, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David; Arnold, Leggy A.

    2013-01-01

    A high throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes to modulate gene regulation mediated by VDR. The peroxisome proliferator-activated receptor δ (PPARδ) agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations higher than 12.1 µM. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor (AR). Surprisingly, GW0742 behaved as PPAR agonist/antagonist activating transcription at lower concentration and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742+ increased fluorescence intensity and fluorescence polarization at an excitation wavelength of 595 nm and emission wavelength of 615 nm in a dose dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3 and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D3. PMID:23713684

  19. Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists.

    PubMed

    Berg, K A; Maayani, S; Goldfarb, J; Clarke, W P

    1998-12-15

    There is now considerable evidence that a single receptor subtype can couple to multiple effector pathways within a cell. Recently, Kenakin proposed a new concept, termed "agonist-directed trafficking of receptor stimulus", that suggests that agonists may be able to selectively activate a subset of multiple signaling pathways coupled to a single receptor subtype. 5-HT2A and 5-HT2C receptors couple to phospholipase C-(PLC) mediated inositol phosphate (IP) accumulation and PLA2-mediated arachidonic acid (AA) release. Relative efficacies of agonists (referenced to 5-HT) differed depending upon whether IP accumulation or AA release was measured. For the 5-HT2C receptor system, some agonists (e.g. TFMPP) preferentially activated the PLC-IP pathway, whereas others (e.g. LSD) favored PLA2-AA. As expected, EC50's of agonists did not differ between pathways. For the 5-HT2A receptor system, all agonists tested had greater relative efficacy for PLA2-AA than for PLC-IP. In contrast, relative efficacies were not different for 5-HT2A agonists when sequential effects in a pathway were measured (IP accumulation vs. calcium mobilization). These data strongly support the agonist-directed trafficking hypothesis.

  20. Selexipag, a selective prostacyclin receptor agonist in pulmonary arterial hypertension: a pharmacology review.

    PubMed

    Honorato Pérez, Jesús

    2017-07-01

    Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest. Management of pulmonary arterial hypertension (PAH) includes specific drug therapy with calcium channel blockers in vasoreactive patients, or drugs approved for PAH in non-reactive patients that target the endothelin, nitric-oxide and prostacyclin pathways. Areas covered: The review covers receptor selectivity, pharmacokinetics, pharmacodynamics and adverse effects (AEs) of intravenous (IV) epoprostenol (synthetic prostacyclin); the prostacyclin analogs iloprost, beraprost, and treprostinil administered by IV, subcutaneous, inhaled or oral routes; and the oral selective prostacyclin receptor agonist selexipag. Expert commentary: Development of a selective prostacyclin receptor agonist has aimed at identifying compounds with improved pharmacological properties. The high selectivity of selexipag, and its active metabolite ACT-333679, for the prostacyclin receptor, in conjunction with pharmacokinetic properties that reduce peak-trough fluctuations and the up-titration regimen used at the start of treatment, are collectively considered to minimize AEs associated with prostacyclin use. In a large phase 3 study, selexipag-associated AEs were consistent with those observed with drugs that target the prostacyclin pathway, and mainly mild to moderate in severity. The dosing flexibility afforded by oral selexipag may facilitate achieving the maximum therapeutic effect with acceptable tolerability in patients with PAH.

  1. The serotonin 5-HT₁A receptor agonist tandospirone improves executive function in common marmosets.

    PubMed

    Baba, Satoko; Murai, Takeshi; Nakako, Tomokazu; Enomoto, Takeshi; Ono, Michiko; Shimizu, Isao; Ikeda, Kazuhito

    2015-01-01

    Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40 mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1-0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1-0.3mg/kg) or haloperidol (0.1-0.3mg/kg) did not improve animals' performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1-0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

    SciTech Connect

    Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong

    2012-06-28

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.

  3. α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia.

    PubMed

    Freedman, Robert

    2014-01-01

    α7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of α7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia. Further development of this therapeutic strategy requires assessment of interactions with patients' heavy cigarette smoking and the relationship of this mechanism to the therapeutic effects of clozapine and olanzapine, both highly effective therapeutics with significant side effects.

  4. Effects of long-term treatment with the luteinizing hormone-releasing hormone (LHRH) agonist Decapeptyl and the LHRH antagonist Cetrorelix on the levels of pituitary LHRH receptors and their mRNA expression in rats

    PubMed Central

    Horvath, Judit E.; Bajo, Ana M.; Schally, Andrew V.; Kovacs, Magdolna; Herbert, Francine; Groot, Kate

    2002-01-01

    The effects of depot formulations of the luteinizing hormone-releasing hormone (LHRH) agonist Decapeptyl (25 μg/day) for 30 days or LHRH antagonist Cetrorelix pamoate (100 μg/day) for 30 days and daily injections of 100 μg of Decapeptyl for 10 days on the expression of mRNA for pituitary LHRH receptor (LHRH-R) and the levels of LHRH-R protein were evaluated in rats. Serum sex steroid concentrations and the weights of the reproductive organs were greatly reduced in all groups treated with analogs, demonstrating an efficient blockade of the pituitary–gonadal axis. Decapeptyl microcapsules elevated serum LH in female rats, but decreased it in male rats. LHRH-R mRNA expression in female pituitaries was reduced to 41% and 56–65% on days 10 and 30, respectively, whereas LHRH-R protein was 64% of control on day 10 and returned to pretreatment levels on day 30. Decapeptyl microcapsules reduced LHRH-R mRNA expression in male pituitaries to 58% on day 30 but not LHRH-R protein. Daily injections of Decapeptyl caused a desensitization of LH responses in female rats, while raising LHRH-R mRNA expression in female rats by 23% and LHRH-R protein levels by 119%. Cetrorelix pamoate reduced serum LH in female rats and diminished LHRH-R mRNA to 30% and 26% and LHRH-R protein to 57% and 48% on days 10 and 30, respectively. Elevated LHRH-R protein levels of ovariectomized rats were reduced after 10-day treatment with Cetrorelix or 100 μg/day Decapeptyl. Thus, changes in the mRNA expression after treatment with Cetrorelix, but not always Decapeptyl, paralleled those of LHRH-R protein. The inhibitory effect of Cetrorelix on serum LH, pituitary LHRH-R mRNA, and LHRH-R protein was greater than that of Decapeptyl. PMID:12409615

  5. Cardiovascular selectivity of adenosine receptor agonists in anaesthetized dogs.

    PubMed Central

    Gerencer, R. Z.; Finegan, B. A.; Clanachan, A. S.

    1992-01-01

    1. In order to determine the relevance of adenosine (Ado) receptor classification obtained from in vitro methods to the cardiovascular actions of Ado agonists in vivo, the cardiovascular effects of adenosine 5'-monophosphate (AMP), N6-cyclohexyladenosine (CHA, 400 fold A1-selective), 5'-N-ethyl-carboxamidoadenosine (NECA, A1 approximately A2) and 2-phenylaminoadenosine (PAA, 5 fold A2-selective) were compared in open-chest, fentanyl-pentobarbitone anaesthetized dogs. 2. Graded doses of CHA (10 to 1000 micrograms kg-1), NECA (0.5 to 100 micrograms kg-1) or PAA (0.1 to 20 micrograms kg-1) were administered intravenously and changes in haemodynamics and myocardial contractility were assessed 10 min following each dose. The effects of graded infusions of AMP (200 to 1000 micrograms kg-1 min-1) were also evaluated. 3. AMP and each of the Ado analogues (NECA > PAA > CHA) increased the systemic vascular conductance index (SVCI) in a dose-dependent manner and reduced mean arterial pressure (MAP). At doses causing similar increases in SVCI, these agonists caused (i) similar reflex increases in heart rate (HR) and cardiac index (CI) and decreases in AV conduction interval (AVi) and (ii) similar increases in coronary vascular conductance (CVC). 4. After cardiac autonomic blockade with atropine (0.2 mg kg-1) and propranolol (1 mg kg-1), AMP, CHA and PAA still increased SVCI and CVC and decreased MAP. CHA and PAA had no marked effects on HR, CI or AVi. As in the absence of cardiac autonomic blockade, equieffective vasodilator doses of CHA and PAA had identical effects on CVC, CI and AVi.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1467827

  6. The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

    PubMed

    Frank, Guido K W; Shott, Megan E; Hagman, Jennifer O; Schiel, Marissa A; DeGuzman, Marisa C; Rossi, Brogan

    2017-04-01

    Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated. © 2017 Wiley Periodicals, Inc.

  7. Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of μ-opioid receptors and dynamin-2

    PubMed Central

    Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A.; Yoburn, Byron C.

    2007-01-01

    It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal μ-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter τ estimated. Mice were injected with the irreversible μ-opioid receptor antagonist clocinnamox (0.32–25.6mg/kg, i.p), and 24h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine > morphine > oxycodone. Other mice were infused for 7 days with oxycodone (10–150 mg/kg/day, s.c.) or etorphine (50–250ug/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal μ-opioid receptors, while etorphine produced ≈ 40% reduction in μ-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with

  8. Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway.

    PubMed

    Thompson, Aiysha; Kanamarlapudi, Venkateswarlu

    2015-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist-induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist-induced human GLP-1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence and luciferase assays to determine cAMP production, intracellular Ca(2+) accumulation and ERK phosphorylation. Agonist-induced hGLP-1R internalisation is dependent on caveolin-1 and dynamin. Inhibition of the Gαq pathway but not the Gαs pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149M and small-molecule agonists (compound 2 and compound B), which activate only the Gαs pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Gαq pathway, PKC and ERK phosphorylation significantly reduced agonist-induced hGLP-1R internalisation. These inhibitors also suppressed agonist-induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Gαq pathway in the hGLP-1R internalisation. In summary, agonist-induced hGLP-1R internalisation is mediated by the Gαq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic β-cells, indicating the importance of GLP-1 internalisation for insulin secretion.

  9. Activation of single heteromeric GABAA receptor ion channels by full and partial agonists

    PubMed Central

    Mortensen, Martin; Kristiansen, Uffe; Ebert, Bjarke; Frølund, Bente; Krogsgaard-Larsen, Povl; Smart, Trevor G

    2004-01-01

    The linkage between agonist binding and the activation of a GABAA receptor ion channel is yet to be resolved. This aspect was examined on human recombinant α1β2γ2S GABAA receptors expressed in human embryonic kidney cells using the following series of receptor agonists: GABA, isoguvacine, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), isonipecotic acid, piperidine-4-sulphonic acid (P4S), imidazole-4-acetic acid (IAA), 5-(4-piperidyl)-3-isothiazolol (thio-4-PIOL) and 5-(4-piperidyl)-3-isoxazolol (4-PIOL). Whole-cell concentration–response curves enabled the agonists to be categorized into four classes based upon their maximum responses. Single channel analyses revealed that the channel conductance of 25–27 pS was unaffected by the agonists. However, two open states were resolved from the open period distributions with mean open times reduced 5-fold by the weakest partial agonists. Using saturating agonist concentrations, estimates of the channel shutting rate, α, ranged from 200 to 600 s−1. The shut period distributions were described by three or four components and for the weakest partial agonists, the interburst shut periods increased whilst the mean burst durations and longest burst lengths were reduced relative to the full agonists. From the burst analyses, the opening rates for channel activation, β, and the total dissociation rates, k−1, for the agonists leaving the receptor were estimated. The agonist efficacies were larger for the full agonists (E ∼7−9) compared to the weak partial agonists (∼0.4–0.6). Overall, changes in agonist efficacy largely determined the different agonist profiles with contributions from the agonist affinities and the degree of receptor desensitization. From this we conclude that GABAA receptor activation does not occur in a switch-like manner since the agonist recognition sites are flexible, accommodating diverse agonist structures which differentially influence the opening and shutting rates of the ion

  10. Exposure to D2-like dopamine receptor agonists inhibits swimming in Daphnia magna.

    PubMed

    Barrozo, Enrico R; Fowler, David A; Beckman, Matthew L

    2015-10-01

    Daphnia are freshwater crustaceans that have been used for decades in ecotoxicology research. Despite the important role that Daphnia have played in environmental toxicology studies, very little is known about the neurobiology of Daphnia. Although many studies have investigated the swimming movements of these "water fleas", few studies have examined the underlying neurochemical basis for these movements. To characterize the locomotor effect of drugs in Daphnia, a two-dimensional video imaging tool was developed and animal tracking was performed with freely available software, CTRAX. Due to the central role that dopamine plays in the movement of animals, we sought to determine the role of dopamine receptor signaling in Daphnia movement by characterizing the effect of ten drugs that are agonists or antagonists of dopamine receptors. At 1, 2, and 6h of treatment with a 10μM drug, several dopamine receptor agonists with documented effects on the D2-like class of receptors decreased the movement. Further, we determined behavioral inhibition values (IC50) at 1h of treatment for (1R,3S)-1-(aminomethyl)-3-phenyl-3,4-dihydro-1H-isochromene-5,6-diol (A68930) to be 1.4μM and for bromocriptine to be 6.6μM. This study describes a new method to study Daphnia swimming and establishes this organism as a useful model for studies of dopaminergic signaling. Specifically, this study shows that a dopamine receptor signaling pathway, mediated by putative D2-like receptors, is involved in the control of Daphnia swimming behavior. Due to its ease of use and its rich motor program we propose that Daphnia should be considered for future studies of dopamine neuron toxicity and protection. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor.

    PubMed

    Shi, Ying; Sheng, Rong; Zhong, Tingting; Xu, Yu; Chen, Xiaopan; Yang, Dong; Sun, Yi; Yang, Fenyan; Hu, Yongzhou; Zhou, Naiming

    2012-01-01

    The histamine H3 receptor (H3R) has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine) and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine) at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.

  12. Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists

    NASA Astrophysics Data System (ADS)

    de Marino, Simona; Carino, Adriana; Masullo, Dario; Finamore, Claudia; Marchianò, Silvia; Cipriani, Sabrina; di Leva, Francesco Saverio; Catalanotti, Bruno; Novellino, Ettore; Limongelli, Vittorio; Fiorucci, Stefano; Zampella, Angela

    2017-02-01

    Bile acids are extensively investigated for their potential in the treatment of human disorders. The liver X receptors (LXRs), activated by oxysterols and by a secondary bile acid named hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In addition to LXRs, HDCA has been also shown to function as ligand for GPBAR1, a G protein coupled receptor for secondary bile acids whose activation represents a promising approach to liver steatosis. In the present study, we report a library of HDCA derivatives endowed with modulatory activity on the two receptors. The lead optimization of HDCA moiety was rationally driven by the structural information on the binding site of the two targets and results from pharmacological characterization allowed the identification of hyodeoxycholane derivatives with selective agonistic activity toward LXRα and GPBAR1 and notably to the identification of the first example of potent dual LXRα/GPBAR1 agonists. The new chemical entities might hold utility in the treatment of dyslipidemic disorders.

  13. Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists

    PubMed Central

    De Marino, Simona; Carino, Adriana; Masullo, Dario; Finamore, Claudia; Marchianò, Silvia; Cipriani, Sabrina; Di Leva, Francesco Saverio; Catalanotti, Bruno; Novellino, Ettore; Limongelli, Vittorio; Fiorucci, Stefano; Zampella, Angela

    2017-01-01

    Bile acids are extensively investigated for their potential in the treatment of human disorders. The liver X receptors (LXRs), activated by oxysterols and by a secondary bile acid named hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In addition to LXRs, HDCA has been also shown to function as ligand for GPBAR1, a G protein coupled receptor for secondary bile acids whose activation represents a promising approach to liver steatosis. In the present study, we report a library of HDCA derivatives endowed with modulatory activity on the two receptors. The lead optimization of HDCA moiety was rationally driven by the structural information on the binding site of the two targets and results from pharmacological characterization allowed the identification of hyodeoxycholane derivatives with selective agonistic activity toward LXRα and GPBAR1 and notably to the identification of the first example of potent dual LXRα/GPBAR1 agonists. The new chemical entities might hold utility in the treatment of dyslipidemic disorders. PMID:28233865

  14. Evidence that antipsychotic drugs are inverse agonists at D2 dopamine receptors.

    PubMed

    Hall, D A; Strange, P G

    1997-06-01

    1. The effects of a number of D2-like dopamine receptor antagonists have been determined on forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing the human D2short dopamine receptor (CHO-D2S cells). 2. Dopamine inhibited the effect of forskolin (as expected for a D2 receptor). However, all of the antagonists tested, apart from UH232 and (-)-butaclamol, were able to increase cyclic AMP accumulation above the forskolin control level. (+)-Butaclamol elicited a similar stimulation of forskolin-stimulated cyclic AMP accumulation in a CHO cell line expressing human D2long dopamine receptors whereas it exhibited no stimulating effect on forskolin-stimulated cyclic AMP accumulation in untransfected CHO-K1 cells. 3. There was a strong correlation between the EC50 values of these compounds for potentiation of cyclic AMP accumulation and their Ki values from radioligand binding experiments in CHO-D2S cells. 4. The effects of both (+)-butaclamol and dopamine in CHO-D2S cells were inhibited by pre-treatment with pertussis toxin indicating a role for Gi/Go proteins. 5. UH232 did not significantly affect forskolin-stimulated cyclic AMP accumulation but this substance was able to inhibit the effects of both dopamine and (+)-butaclamol in a concentration-dependent manner. Thus the effects of (+)-butaclamol on forskolin-stimulated cyclic AMP accumulation are mediated directly via the D2 receptor rather than by reversal of the effects of an endogenous agonist. 6. These data suggest that the D2 dopamine receptor antagonists tested here, many of which are used clinically as antipsychotic drugs, are in fact inverse agonists at human D2 dopamine receptors.

  15. Tetrahydroquinoline glucocorticoid receptor agonists: discovery of a 3-hydroxyl for improving receptor selectivity.

    PubMed

    Roach, Steven L; Higuchi, Robert I; Hudson, Andrew R; Adams, Mark E; Syka, Peter M; Mais, Dale E; Miner, Jeffrey N; Marschke, Keith B; Zhi, Lin

    2011-01-01

    We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists. Copyright © 2010 Elsevier Ltd. All rights reserved.

  16. The Protective Role of PAC1-Receptor Agonist Maxadilan in BCCAO-Induced Retinal Degeneration.

    PubMed

    Vaczy, A; Reglodi, D; Somoskeoy, T; Kovacs, K; Lokos, E; Szabo, E; Tamas, A; Atlasz, T

    2016-10-01

    A number of studies have proven that pituitary adenylate cyclase activating polypeptide (PACAP) is protective in neurodegenerative diseases. Permanent bilateral common carotid artery occlusion (BCCAO) causes severe degeneration in the rat retina. In our previous studies, protective effects were observed with PACAP1-38, PACAP1-27, and VIP but not with their related peptides, glucagon, or secretin in BCCAO. All three PACAP receptors (PAC1, VPAC1, VPAC2) appear in the retina. Molecular and immunohistochemical analysis demonstrated that the retinoprotective effects are most probably mainly mediated by the PAC1 receptor. The aim of the present study was to investigate the retinoprotective effects of a selective PAC1-receptor agonist maxadilan in BCCAO-induced retinopathy. Wistar rats were used in the experiment. After performing BCCAO, the right eye was treated with intravitreal maxadilan (0.1 or 1 μM), while the left eye was injected with vehicle. Sham-operated rats received the same treatment. Two weeks after the operation, retinas were processed for standard morphometric and molecular analysis. Intravitreal injection of 0.1 or 1 μM maxadilan caused significant protection in the thickness of most retinal layers and the number of cells in the GCL compared to the BCCAO-operated eyes. In addition, 1 μM maxadilan application was more effective than 0.1 μM maxadilan treatment in the ONL, INL, IPL, and the entire retina (OLM-ILM). Maxadilan treatment significantly decreased cytokine expression (CINC-1, IL-1α, and L-selectin) in ischemia. In summary, our histological and molecular analysis showed that maxadilan, a selective PAC1 receptor agonist, has a protective role in BCCAO-induced retinal degeneration, further supporting the role of PAC1 receptor conveying the retinoprotective effects of PACAP.

  17. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Blast traumatic brain injury induced cognitive deficits are attenuated by pre- or post-injury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4

    PubMed Central

    Tweedie, David; Rachmany, Lital; Rubovitch, Vardit; Li, Yazhou; Holloway, Harold W.; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.; Perez, Evelyn; Hoffer, Barry J.; Pick, Chaim G.; Greig, Nigel H.

    2015-01-01

    Background Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently there are no approved drugs for blast brain injury. Methods Exendin-4, administered subcutaneously, was evaluated as a pre-treatment (48 hours) and post-injury treatment (2 hours) on neurodegeneration, behaviors and gene expressions in a murine open field model of blast injury. Results B-TBI induced neurodegeneration, changes in cognition and genes expressions linked to dementia disorders. Exendin-4, administered pre- or post-injury ameliorated B-TBI-induced neurodegeneration at 72 hours, memory deficits from days 7–14 and attenuated genes regulated by blast at day 14 post-injury. Conclusions The present data suggest shared pathological processes between concussive and B-TBI, with endpoints amenable to beneficial therapeutic manipulation by exendin-4. B-TBI-induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiological studies of Barnes and co-workers who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life. PMID:26327236

  19. Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner.

    PubMed

    Blume, Lawrence C; Leone-Kabler, Sandra; Luessen, Deborah J; Marrs, Glen S; Lyons, Erica; Bass, Caroline E; Chen, Rong; Selley, Dana E; Howlett, Allyn C

    2016-11-01

    Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB1 Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1 R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1 R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1 R by a dynamin- and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1 R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30-120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB1 Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)-mediated increase in cell surface CB1 Rs, which is postulated to be as a result of rimonabant effects on 'non-agonist-driven' internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface.

  20. Direct visualisation of internalization of the adenosine A3 receptor and localization with arrestin3 using a fluorescent agonist.

    PubMed

    Stoddart, Leigh A; Vernall, Andrea J; Briddon, Stephen J; Kellam, Barrie; Hill, Stephen J

    2015-11-01

    Fluorescence based probes provide a novel way to study the dynamic internalization process of G protein-coupled receptors (GPCRs). Recent advances in the rational design of fluorescent ligands for GPCRs have been used here to generate new fluorescent agonists containing tripeptide linkers for the adenosine A3 receptor. The fluorescent agonist BY630-X-(D)-A-(D)-A-G-ABEA was found to be a highly potent agonist at the adenosine A3 receptor in both reporter gene (pEC50 = 8.48 ± 0.09) and internalization assays (pEC50 = 7.47 ± 0.11). Confocal imaging studies showed that BY630-X-(D)-A-(D)-A-G-ABEA was internalized with A3 linked to yellow fluorescent protein, which was blocked by the competitive antagonist MRS1220. Internalization of untagged adenosine A3 could also be visualized with BY630-X-(D)-A-(D)-A-G-ABEA treatment. Further, BY630-X-(D)-A-(D)-A-G-ABEA stimulated the formation of receptor-arrestin3 complexes and was found to localize with these intracellular complexes. This highly potent agonist with excellent imaging properties should be a valuable tool to study receptor internalization. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'.

  1. Intrinsic Relative Activities of Opioid Agonists in Activating Gα proteins and Internalizing Receptor: Differences between Human and Mouse Receptors

    PubMed Central

    DiMattio, Kelly M.; Ehlert, Frederick J.; Liu-Chen, Lee-Yuan

    2015-01-01

    Several investigators recently identified biased opioid receptor (KOP receptor) agonists. However, no comprehensive study of the functional selectivity of available KOP receptor agonists at the human and mouse KOP receptors (hKOP receptor and mKOP receptor, respectively) has been published. Here we examined the ability of over 20 KOP receptor agonists to activate G proteins and to internalize the receptor. Clonal neuro-2a mouse neuroblastoma (N2a) cells stably transfected with the hKOP receptor or mKOP receptor were used. We employed agonist-induced [35S]GTPγS binding and KOP receptor internalization as measures of activation of G protein and β-arrestin pathways, respectively. The method of Ehlert and colleagues was used to quantify intrinsic relative activities at G protein activation (RAi−G) and receptor internalization (RAi−I) and the degree of functional selectivity between the two [Log RAi−G − Log RAi−I, RAi−G/RAi−I and bias factor]. The parameter, RAi, represents a relative estimate of agonist affinity for the active receptor state that elicits a given response. The endogenous ligand dynorphin A (1–17) was designated as the balanced ligand with a bias factor of 1. Interestingly, we found that there were species differences in functional selectivity. The most striking differences were for 12-epi-salvinorin A, U69,593, and ICI-199,441. 12-Epi-salvinorin A was highly internalization-biased at the mKOP receptor, but apparently G protein-biased at hKOP receptor. U69,593 was much more internalization-biased at mKOP receptor than hKOP receptor. ICI199,441 showed internalization-biased at the mKOP receptor and G protein-biased at the hKOP receptor. Possible mechanisms for the observed species differences are discussed. PMID:26057692

  2. Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists.

    PubMed

    Miczek, K A; Hussain, S; Faccidomo, S

    1998-09-01

    One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with

  3. Trialkyltin Rexinoid-X Receptor Agonists Selectively Potentiate Thyroid Hormone Induced Programs of Xenopus laevis Metamorphosis.

    PubMed

    Mengeling, Brenda J; Murk, Albertinka J; Furlow, J David

    2016-07-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the environment prompted us to test whether they could also affect TH signaling. Both trialkyltins induced the integrated luciferase reporter alone and potentiated TH activation at low doses. Trimethyltin, which is not an RXR agonist, did not. We turned to a simple, robust, and specific in vivo model system of TH action: metamorphosis of Xenopus laevis, the African clawed frog. Using a precocious metamorphosis assay, we found that 1nM TBT and TPT, but not trimethyltin, greatly potentiated the effect of TH treatment on resorption phenotypes of the tail, which is lost at metamorphosis, and in the head, which undergoes extensive remodeling including gill loss. Consistent with these responses, TH-induced caspase-3 activation in the tail was enhanced by cotreatment with TBT. Induction of a transgenic reporter gene and endogenous collagenase 3 (mmp13) and fibroblast-activating protein-α (fap) genes were not induced by TBT alone, but TH induction was significantly potentiated by TBT. However, induction of other TH receptor target genes such as TRβ and deiodinase 3 by TH were not affected by TBT cotreatment. These data indicate that trialkyltins that can function as RXR agonists can selectively potentiate gene expression and resultant morphological programs directed by TH signaling in vivo.

  4. Mechanical stress activates NMDA receptors in the absence of agonists

    PubMed Central

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

    2017-01-01

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca2+ influx. Extracellular Mg2+ at 2 mM did not significantly affect the shear induced Ca2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI. PMID:28045032

  5. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury.

    PubMed

    Goto, Hiromasa; Nomiyama, Takashi; Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio; Kawamori, Ryuzo; Fujitani, Yoshio; Hirose, Takahisa; Watada, Hirotaka

    2011-02-04

    Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease.

    PubMed

    Landreth, Gary; Jiang, Qingguang; Mandrekar, Shweta; Heneka, Michael

    2008-07-01

    Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARgamma agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARgamma agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARgamma represents an important new therapeutic target in treating AD.

  7. Exploring pharmacological activities and signaling of morphinans substituted in position 6 as potent agonists interacting with the μ opioid receptor

    PubMed Central

    2014-01-01

    Background Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. Results This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. Conclusion Development of such novel chemotypes by targeting

  8. Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

    PubMed Central

    Sloop, Kyle W.; Willard, Francis S.; Brenner, Martin B.; Ficorilli, James; Valasek, Kathleen; Showalter, Aaron D.; Farb, Thomas B.; Cao, Julia X.C.; Cox, Amy L.; Michael, M. Dodson; Gutierrez Sanfeliciano, Sonia Maria; Tebbe, Mark J.; Coghlan, Michael J.

    2010-01-01

    OBJECTIVE The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. RESEARCH DESIGN AND METHODS Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. RESULTS Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. CONCLUSIONS These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization. PMID:20823098

  9. Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function.

    PubMed

    Pradhan, Amynah A; Perroy, Julie; Walwyn, Wendy M; Smith, Monique L; Vicente-Sanchez, Ana; Segura, Laura; Bana, Alia; Kieffer, Brigitte L; Evans, Christopher J

    2016-03-23

    Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor-Ca(2+)channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560) preferentially recruit

  10. Hydrogen/Deuterium Exchange Reveals Distinct Agonist/Partial Agonist Receptor Dynamics within the intact Vitamin D Receptor/Retinoid X Receptor Heterodimer

    PubMed Central

    Zhang, Jun; Chalmers, Michael J.; Stayrook, Keith R.; Burris, Lorri L.; Garcia-Ordonez, Ruben D.; Pascal, Bruce D.; Burris, Thomas P.; Dodge, Jeffery A.; Griffin, Patrick R.

    2010-01-01

    Summary Regulation of nuclear receptor (NR) activity is driven by alterations in the conformational dynamics of the receptor upon ligand binding. Previously we demonstrated that hydrogen/deuterium exchange (HDX) can be applied to determine novel mechanism of action of PPARγ ligands and in predicting tissue specificity of selective estrogen receptor modulators. Here we applied HDX to probe the conformational dynamics of the ligand binding domain (LBD) of the vitamin D receptor (VDR) upon binding its natural ligand 1α,25-dihydroxyvitamin D3 (1,25D3), and two analogs, alfacalcidol and ED-71. Comparison of HDX profiles from ligands in complex with the LBD with full-length receptor bound to its cognate receptor retinoid X receptor (RXR) revealed unique receptor dynamics that could not be inferred from static crystal structures. These results demonstrate that ligands modulate the dynamics of the heterodimer interface as well as providing insight into the role of AF-2 dynamics in the action of VDR partial agonists. PMID:20947021

  11. Desensitization of functional µ-opioid receptors increases agonist off-rate.

    PubMed

    Williams, John T

    2014-07-01

    Desensitization of µ-opioid receptors (MORs) develops over 5-15 minutes after the application of some, but not all, opioid agonists and lasts for tens of minutes after agonist removal. The decrease in function is receptor selective (homologous) and could result from 1) a reduction in receptor number or 2) a decrease in receptor coupling. The present investigation used photolysis of two caged opioid ligands to examine the kinetics of MOR-induced potassium conductance before and after MOR desensitization. Photolysis of a caged antagonist, carboxynitroveratryl-naloxone (caged naloxone), blocked the current induced by a series of agonists, and the time constant of decline was significantly decreased after desensitization. The increase in the rate of current decay was not observed after partial blockade of receptors with the irreversible antagonist, β-chlornaltrexamine (β-CNA). The time constant of current decay after desensitization was never more rapid than 1 second, suggesting an increased agonist off-rate rather than an increase in the rate of channel closure downstream of the receptor. The rate of G protein-coupled K(+) channel (GIRK) current activation was examined using photolysis of a caged agonist, carboxynitrobenzyl-tyrosine-[Leu(5)]-enkephalin. After acute desensitization or partial irreversible block of MORs with β-CNA, there was an increase in the time it took to reach a peak current. The decrease in the rate of agonist-induced GIRK conductance was receptor selective and dependent on receptor number. The results indicate that opioid receptor desensitization reduced the number of functional receptor and that the remaining active receptors have a reduced agonist affinity.

  12. α(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking.

    PubMed

    Smith, Rachel J; Aston-Jones, Gary

    2011-10-15

    Drug-associated cues can elicit stress-like responses in addicted individuals, indicating that cue- and stress-induced drug relapse may share some neural mechanisms. It is unknown whether α(2) adrenergic receptor agonists, which are known to attenuate stress-induced reinstatement of drug seeking in rats, also reduce cue-induced reinstatement. Rats were tested for reinstatement of drug seeking following cocaine self-administration and extinction. We first evaluated the effects of clonidine, an agonist at α(2) and imidazoline-1 (I(1)) receptors, on relapse to cocaine seeking. To explore possible mechanisms of clonidine's effects, we then tested more specific α(2) or I(1) agonists, postsynaptic adrenergic receptor (α(1) and β) antagonists, and corticotropin-releasing factor receptor-1 antagonists. We found that clonidine, and the more selective α(2) agonists UK-14,304 and guanfacine, decreased cue-induced reinstatement of cocaine seeking. The specific I(1) receptor agonist moxonidine reduced cue-induced as well as cocaine-induced reinstatement. Clonidine or moxonidine effects on cue-induced reinstatement were reversed by the selective α(2) receptor antagonist RS-79948, indicating a role for α(2) receptors. Prazosin and propranolol, antagonists at the α(1) and β receptor, respectively, reduced cue-induced reinstatement only when administered in combination. Finally, the corticotropin-releasing factor receptor-1 antagonist CP-154,526 reduced cue-induced reinstatement, as previously observed for stress-induced reinstatement, indicating possible overlap between stress and cue mechanisms. These results indicate that α(2) and I(1) receptor agonists are novel therapeutic options for prevention of cue-induced cocaine relapse. Given that α(2) receptor stimulation is associated with sedation in humans, the I(1) agonist moxonidine seems to have substantial potential for treating addictive disorders. Copyright © 2011 Society of Biological Psychiatry. Published by

  13. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

    PubMed Central

    Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; Unnasch, Thomas R.

    2016-01-01

    Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. PMID:27300294

  14. Fluorescence characteristics of hydrophobic partial agonist probes of the cholecystokinin receptor.

    PubMed

    Harikumar, Kaleeckal G; Pinon, Delia I; Miller, Laurence J

    2006-04-01

    Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.

  15. Population pharmacokinetics and pharmacodynamics of peptidic erythropoiesis receptor agonist (ERA) in healthy volunteers.

    PubMed

    Woo, Sukyung; Krzyzanski, Wojciech; Duliege, Anne-Marie; Stead, Richard B; Jusko, William J

    2008-01-01

    Peptidic erythropoiesis receptor agonist is a synthetic, PEGylated peptide that can promote red blood cell production upon binding to the erythropoietin receptor. The objective of this study was to characterize the pharmacokinetics and erythropoietic effects of peptidic erythropoiesis receptor agonist in healthy volunteers. Plasma concentrations of peptidic erythropoiesis receptor agonist and pharmacodynamic responses were obtained after single intravenous injections at doses of 0.025, 0.05, and 0.1 mg/kg. Population pharmacokinetic/pharmacodynamic modeling was performed using NONMEM. Peptidic erythropoiesis receptor agonist exhibited nonlinear pharmacokinetics described by a 1-compartment model with parallel elimination by Michaelis-Menten and linear processes. A catenary, life span-based, indirect response model reflecting bone marrow erythroid and blood cells reflected the pharmacodynamics of peptidic erythropoiesis receptor agonist. A modest tolerance and rebound phenomenon in reticulocytes was modeled with negative feedback regulation related to hemoglobin. This pharmacokinetic/pharmacodynamic model well characterized the prolonged disposition, intrinsic pharmacologic parameters, and typical hematological system properties following single doses of peptidic erythropoiesis receptor agonist in normal subjects.

  16. Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors

    SciTech Connect

    Neumeier, Markus; Weigert, Johanna; Schaeffler, Andreas; Weiss, Thomas; Kirchner, Stefan; Laberer, Sabine; Schoelmerich, Juergen; Buechler, Christa . E-mail: christa.buechler@klinik.uni-regensburg.de

    2005-09-02

    The adiponectin receptors AdipoR1 and AdipoR2 have been identified to mediate the insulin-sensitizing effects of adiponectin. Although AdipoR2 was suggested to be the main receptor for this adipokine in hepatocytes, AdipoR1 protein is highly abundant in primary human hepatocytes and hepatocytic cell lines. Nuclear receptors are main regulators of lipid metabolism and activation of peroxisome proliferator-activated receptor {alpha} and {gamma}, retinoid X receptor (RXR), and liver X receptor (LXR) by specific ligands may influence AdipoR1 abundance. AdipoR1 protein is neither altered by RXR or LXR agonists nor by pioglitazone. In contrast, fenofibric acid reduces AdipoR1 whereas hepatotoxic troglitazone upregulates AdipoR1 protein in HepG2 cells. Taken together this work shows for the first time that AdipoR1 protein is expressed in human hepatocytes but that it is not a direct target gene of nuclear receptors. Elevated AdipoR1 induced by hepatotoxic troglitazone may indicate a role of this receptor in adiponectin-mediated beneficial effects in liver damage.

  17. Electrophysiological perspectives on the therapeutic use of nicotinic acetylcholine receptor partial agonists.

    PubMed

    Papke, Roger L; Trocmé-Thibierge, Caryn; Guendisch, Daniela; Al Rubaiy, Shehd Abdullah Abbas; Bloom, Stephen A

    2011-05-01

    Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)(2)(β2)(3), (α4)(3)(β2)(2), and (α4)(2)(β2)(2)α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.

  18. Neuroprotective actions of GR89696, a highly potent and selective kappa-opioid receptor agonist.

    PubMed Central

    Birch, P. J.; Rogers, H.; Hayes, A. G.; Hayward, N. J.; Tyers, M. B.; Scopes, D. I.; Naylor, A.; Judd, D. B.

    1991-01-01

    1. The effect of a novel, highly potent and selective kappa-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2. In the Mongolian gerbil model, administration of GR89696 (3 to 30 micrograms kg-1, s.c.), immediately before and at 4 h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other kappa-agonists, GR86014 (1 mgkg-1, s.c.) and GR91272 (1 mgkg-1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mgkg-1, s.c. Repeated post-treatment with GR89696 (100 micrograms kg-1, s.c.) or GR44821 (10 mgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3. In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 micrograms kg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 micrograms kg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4. The results indicate that the potent kappa-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention. PMID:1657267

  19. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist.

    PubMed

    Gassaway, M M; Rives, M-L; Kruegel, A C; Javitch, J A; Sames, D

    2014-07-15

    Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. However, in spite of three decades of basic and clinical investigations, the molecular target of tianeptine, as well as its mechanism of action, remains elusive. Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (K(i Human) of 383±183 nM and EC(50 Human) of 194±70 nM  and EC(50 Mouse) of 641±120 nM for G-protein activation). Tianeptine was also a full δ-opioid receptor (DOR) agonist, although with much lower potency (EC(50 Human) of 37.4±11.2 μM and EC(50 Mouse) of 14.5±6.6  μM for G-protein activation). In contrast, tianeptine was inactive at the κ-opioid receptor (KOR, both human and rat). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions.

  20. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist

    PubMed Central

    Gassaway, M M; Rives, M-L; Kruegel, A C; Javitch, J A; Sames, D

    2014-01-01

    Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical antidepressant tianeptine already meets in part these clinical goals. However, in spite of three decades of basic and clinical investigations, the molecular target of tianeptine, as well as its mechanism of action, remains elusive. Herein, we report the characterization of tianeptine as a μ-opioid receptor (MOR) agonist. Using radioligand binding and cell-based functional assays, including bioluminescence resonance energy transfer-based assays for G-protein activation and cAMP accumulation, we identified tianeptine as an efficacious MOR agonist (Ki Human of 383±183 nM and EC50 Human of 194±70 nM  and EC50 Mouse of 641±120 nM for G-protein activation). Tianeptine was also a full δ-opioid receptor (DOR) agonist, although with much lower potency (EC50 Human of 37.4±11.2 μM and EC50 Mouse of 14.5±6.6  μM for G-protein activation). In contrast, tianeptine was inactive at the κ-opioid receptor (KOR, both human and rat). On the basis of these pharmacological data, we propose that activation of MOR (or dual activation of MOR and DOR) could be the initial molecular event responsible for triggering many of the known acute and chronic effects of this agent, including its antidepressant and anxiolytic actions. PMID:25026323

  1. The long-acting β2 -adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner.

    PubMed

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-05-01

    Inhaled glucocorticoid (ICS)/long-acting β2 -adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. © 2015 The British Pharmacological Society.

  2. The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner

    PubMed Central

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-01-01

    Background and Purpose Inhaled glucocorticoid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. Experimental Approach BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Key Results Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. Conclusions and Implications These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. PMID:25598440

  3. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

    PubMed

    Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-05-03

    Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

  4. Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors

    PubMed Central

    Koshimizu, Taka-aki; Kashiwazaki, Aki; Taniguchi, Junichi

    2016-01-01

    Reducing Na+ in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na+-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na+ sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na+ increased cell surface [3H]AVP binding and decreased receptor internalization. Substitution of Na+ by Cs+ or NH4+ inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na+ over Cs+. Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations. PMID:27138239

  5. Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification.

    PubMed

    Heightman, Tom D; Scott, Jackie S; Longley, Mark; Bordas, Vincent; Dean, David K; Elliott, Richard; Hutley, Gail; Witherington, Jason; Abberley, Lee; Passingham, Barry; Berlanga, Manuela; de Los Frailes, Maite; Wise, Alan; Powney, Ben; Muir, Alison; McKay, Fiona; Butler, Sharon; Winborn, Kim; Gardner, Christopher; Darton, Jill; Campbell, Colin; Sanger, Gareth

    2007-12-01

    High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.

  6. Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes.

    PubMed

    Whitlock, Brian K; Daniel, Joseph A; Amelse, Lisa L; Tanco, Valeria M; Chameroy, Kelly A; Schrick, F Neal

    2015-01-01

    Kisspeptin receptor (KISS1R) agonists with increased half-life and similar efficacy to kisspeptin in vitro may provide beneficial applications in breeding management of many species. However, many of these agonists have not been tested in vivo. These studies were designed to test and compare the effects of a KISS1R agonist (FTM080) and kisspeptin on luteinizing hormone (LH) in vivo. In experiment 1 (pilot study), sheep were treated with FTM080 (500 pmol/kg BW) or sterile water (VEH) intravenosuly. Blood was collected every 15 min before (1 h) and after (1 h) treatment. In experiment 2, sheep were treated with KP-10 (human Metastin 45-54; 500 pmol/kg BW), one of three dosages of FTM080 (500 (FTM080:500), 2500 (FTM080:2500), or 5000 (FTM080:5000) pmol/kg BW), or VEH intravenously. Blood was collected every 15 min before (1 h) and after (4 h) treatment. In experiment 1, FTM080:500 increased (P < 0.05) plasma LH concentrations when compared to VEH. The area under the curve (AUC) of LH following FTM080:500 treatment was also increased (P < 0.05). In experiment 2, plasma LH concentrations increased (P < 0.05) following treatment with KP-10 and FTM080:5000 when compared to VEH and FTM080:500. The AUC of LH following KP-10 was greater than (P < 0.05) all other treatments and the AUC of LH following FTM080:5000 was greater than (P < 0.05) all treatments except KP-10. These data provide evidence to suggest that FTM080 stimulates the gonadotropic axis of ruminants in vivo. Any increased half-life and comparable efficacy of FTM080 to KP-10 in vitro does not appear to translate to in vivo in sheep.

  7. Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes

    PubMed Central

    Daniel, Joseph A.; Amelse, Lisa L.; Tanco, Valeria M.; Chameroy, Kelly A.; Schrick, F. Neal

    2015-01-01

    Kisspeptin receptor (KISS1R) agonists with increased half-life and similar efficacy to kisspeptin in vitro may provide beneficial applications in breeding management of many species. However, many of these agonists have not been tested in vivo. These studies were designed to test and compare the effects of a KISS1R agonist (FTM080) and kisspeptin on luteinizing hormone (LH) in vivo. In experiment 1 (pilot study), sheep were treated with FTM080 (500 pmol/kg BW) or sterile water (VEH) intravenosuly. Blood was collected every 15 min before (1 h) and after (1 h) treatment. In experiment 2, sheep were treated with KP-10 (human Metastin 45-54; 500 pmol/kg BW), one of three dosages of FTM080 (500 (FTM080:500), 2500 (FTM080:2500), or 5000 (FTM080:5000) pmol/kg BW), or VEH intravenously. Blood was collected every 15 min before (1 h) and after (4 h) treatment. In experiment 1, FTM080:500 increased (P < 0.05) plasma LH concentrations when compared to VEH. The area under the curve (AUC) of LH following FTM080:500 treatment was also increased (P < 0.05). In experiment 2, plasma LH concentrations increased (P < 0.05) following treatment with KP-10 and FTM080:5000 when compared to VEH and FTM080:500. The AUC of LH following KP-10 was greater than (P < 0.05) all other treatments and the AUC of LH following FTM080:5000 was greater than (P < 0.05) all treatments except KP-10. These data provide evidence to suggest that FTM080 stimulates the gonadotropic axis of ruminants in vivo. Any increased half-life and comparable efficacy of FTM080 to KP-10 in vitro does not appear to translate to in vivo in sheep. PMID:26587345

  8. A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis.

    PubMed

    Kao, W; Gu, R; Jia, Y; Wei, Xuemin; Fan, H; Harris, J; Zhang, Zhiyi; Quinn, J; Morand, E F; Yang, Y H

    2014-09-01

    Annexin A1 (AnxA1) is an endogenous anti-inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast-like synoviocytes (FLS). Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type (WT) or AnxA1(-/-) mice and clinical and histopathological manifestations measured 8-11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg(-1) i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL-induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages. Treatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF-α and osteoclast-associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 increased this release. The FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA. © 2014 The British Pharmacological Society.

  9. Repression of gamma-aminobutyric acid type A receptor alpha1 polypeptide biosynthesis requires chronic agonist exposure.

    PubMed

    Miranda, J D; Barnes, E M

    1997-06-27

    Although it is well established that the number of gamma-aminobutyric acid type A (GABAA) receptors declines in cortical neurons exposed to GABAA receptor agonists, the mechanisms responsible for this use-dependent down-regulation remain unclear. Two hypotheses have been proposed: (i) agonist-evoked sequestration and degradation of surface GABAA receptors and (ii) repression of receptor subunit biosynthesis. We have addressed this problem using [35S]Met/Cys pulse-chase labeling of chick cortical neurons in culture and immunoprecipitation and immunoblotting with an antibody (RP4) directed against a GABAA receptor alpha1-(331-381) fusion protein. Exposure of the cells to GABA or isoguvacine for 2 h to 4 days had no effect on the initial rate of 35S incorporation into the GABAA receptor 51-kDa alpha1 polypeptide, but this rate declined by 33% after a 7-day treatment. This is consistent with a previous report (Baumgartner, B. J., Harvey, R. J., Darlison, M. G., and Barnes, E. M. (1994) Mol. Brain Res. 26, 9-17) that a 7-day GABA treatment of this preparation produced a 45% reduction in the alpha1 subunit mRNA level, while a 4-day exposure had no detectable effect. On the other hand, after a 4-day exposure to these agonists, a 30% reduction in the level of the alpha1 polypeptide was observed on immunoblots, similar to that found previously for down-regulation of GABAA receptor ligand-binding sites. Thus, the de novo synthesis of GABAA receptor alpha1 subunits is subject to a delayed use-dependent repression that was observed after, rather than before, the decline in neuronal levels of the polypeptide. Pulse-chase experiments showed a monophasic degradation of the GABAA receptor 35S-alpha1 subunit with a t1/2 = 7.7 h, a process that was unaffected by the addition of GABA to neurons during the chase period. These nascent 35S-labeled polypeptides are presumably diluted into the neuronal pool of unlabeled unassembled alpha1 subunits, which was found to exceed by a 4:1 molar

  10. Relaxant Effects of the Selective Estrogen Receptor Modulator, Bazedoxifene, and Estrogen Receptor Agonists in Isolated Rabbit Basilar Artery.

    PubMed

    Castelló-Ruiz, María; Salom, Juan B; Fernández-Musoles, Ricardo; Burguete, María C; López-Morales, Mikahela A; Arduini, Alessandro; Jover-Mengual, Teresa; Hervás, David; Torregrosa, Germán; Alborch, Enrique

    2016-10-01

    We have previously shown that the selective estrogen receptor modulator, bazedoxifene, improves the consequences of ischemic stroke. Now we aimed to characterize the effects and mechanisms of action of bazedoxifene in cerebral arteries. Male rabbit isolated basilar arteries were used for isometric tension recording and quantitative polymerase chain reaction. Bazedoxifene relaxed cerebral arteries, as 17-β-estradiol, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [estrogen receptor (ER) α agonist], and G1 [G protein-coupled ER (GPER) agonist] did it (4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol > bazedoxifene = G1 > 17-β-estradiol). 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERβ agonist) had no effect. Expression profile of genes encoding for ERα (ESR1), ERβ (ESR2), and GPER was GPER > ESR1 > ESR2. As to the endothelial mechanisms, endothelium removal, N-nitro-L-arginine methyl ester, and indomethacin, did not modify the relaxant responses to bazedoxifene. As to the K channels, both a high-K medium and the Kv blocker, 4-aminopyridine, inhibited the bazedoxifene-induced relaxations, whereas tetraethylammonium (nonselective K channel blocker), glibenclamide (selective KATP blocker) or iberiotoxin (selective KCa blocker) were without effect. Bazedoxifene also inhibited both Ca- and Bay K8644-elicited contractions. Therefore, bazedoxifene induces endothelium-independent relaxations of cerebral arteries through (1) activation of GPER and ERα receptors; (2) increase of K conductance through Kv channels; and (3) inhibition of Ca entry through L-type Ca channels. Such a profile is compatible with the beneficial effects of estrogenic compounds (eg, SERMs) on vascular function and, specifically, that concerning the brain. Therefore, bazedoxifene could be useful in the treatment of cerebral disorders in which the cerebrovascular function is compromised (eg, stroke).

  11. Adenosine A(3) receptor agonist acts as a homeostatic regulator of bone marrow hematopoiesis.

    PubMed

    Hofer, Michal; Pospísil, Milan; Znojil, Vladimír; Holá, Jirina; Vacek, Antonín; Streitová, Denisa

    2007-07-01

    The present study was performed to define the optimum conditions of the stimulatory action of the adenosine A(3) receptor agonist, N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), on bone marrow hematopoiesis in mice. Effects of 2-day treatment with IB-MECA given at single doses of 200nmol/kg twice daily were investigated in normal mice and in mice whose femoral bone marrow cells were either depleted or regenerating after pretreatment with the cytotoxic drug 5-fluorouracil. Morphological criteria were used to determine the proliferation state of the granulocytic and erythroid cell systems. Significant negative correlation between the control proliferation state and the increase of cell proliferation after IB-MECA treatment irrespective of the cell lineage investigated was found. The results suggest the homeostatic character of the induced stimulatory effects and the need to respect the functional state of the target tissue when investigating effects of adenosine receptor agonists under in vivo conditions.

  12. A nicotinic acetylcholine receptor agonist affects honey bee sucrose responsiveness and decreases waggle dancing.

    PubMed

    Eiri, Daren M; Nieh, James C

    2012-06-15

    A nicotinic acetylcholine receptor agonist, imidacloprid, impairs memory formation in honey bees and has general effects on foraging. However, little is known about how this agonist affects two specific aspects of foraging: sucrose responsiveness (SR) and waggle dancing (which recruits nestmates). Using lab and field experiments, we tested the effect of sublethal doses of imidacloprid on (1) bee SR with the proboscis extension response assay, and (2) free-flying foragers visiting and dancing for a sucrose feeder. Bees that ingested imidacloprid (0.21 or 2.16 ng bee(-1)) had higher sucrose response thresholds 1 h after treatment. Foragers that ingested imidacloprid also produced significantly fewer waggle dance circuits (10.5- and 4.5-fold fewer for 50% and 30% sucrose solutions, respectively) 24 h after treatment as compared with controls. However, there was no significant effect of imidacloprid on the sucrose concentrations that foragers collected at a feeder 24 h after treatment. Thus, imidacloprid temporarily increased the minimum sucrose concentration that foragers would accept (short time scale, 1 h after treatment) and reduced waggle dancing (longer time scale, 24 h after treatment). The effect of time suggests different neurological effects of imidacloprid resulting from the parent compound and its metabolites. Waggle dancing can significantly increase colony food intake, and thus a sublethal dose (0.21 ng bee(-1), 24 p.p.b.) of this commonly used pesticide may impair colony fitness.

  13. Small Molecules with Similar Structures Exhibit Agonist, Neutral Antagonist or Inverse Agonist Activity toward Angiotensin II Type 1 Receptor

    PubMed Central

    Hanzawa, Hiroyuki; Nakao, Naoki; Fujino, Masahiro; Imaizumi, Satoshi; Matsuo, Yoshino; Yanagisawa, Hiroaki; Koike, Hiroyuki; Komuro, Issei; Karnik, Sadashiva S.; Saku, Keijiro

    2012-01-01

    Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT1 receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ). PMID:22719858

  14. Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins.

    PubMed

    Melkes, Barbora; Hejnova, Lucie; Novotny, Jiri

    2016-12-01

    There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala(2),N-MePhe(4),Gly(5)-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2. Interestingly, cholesterol depletion strongly enhanced the ability of morphine to elevate receptor mobility but significantly reduced or even eliminated the effect of DAMGO and endomorphin-2, respectively. Moreover, the ability of DAMGO and endomorphin-2 to influence MOR-YFP movement was diminished by pertussis toxin treatment. The results obtained by agonist-stimulated [(35)S]GTPγS binding assays indicated that DAMGO exhibited higher efficacy than morphine and endomorphin-2 did and that the efficacy of DAMGO, contrary to the latter agonists, was enhanced by cholesterol depletion. Overall, our study provides clear evidence that biased MOR agonists diversely affect receptor mobility in plasma membranes as well as MOR/G protein coupling and that the regulatory effect of different ligands depends on the membrane cholesterol content. These findings help to delineate the fundamental properties of MOR regarding their interaction with biased MOR ligands and cognate G proteins.

  15. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy.

    PubMed

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-03-01

    Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy.

  16. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  17. Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy.

    PubMed

    Gallo, S; Gatti, S; Sala, V; Albano, R; Costelli, P; Casanova, E; Comoglio, P M; Crepaldi, T

    2014-04-17

    Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated the cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic of hypoxia, was used to induce cardiac damage in H9c2 cardiomyoblasts, which resulted in reduction of cell viability by (i) caspase-dependent apoptosis and (ii) - surprisingly - autophagy. Blocking either apoptosis with the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone or autophagosome formation with 3-methyladenine prevented loss of cell viability, which suggests that both processes contribute to cardiomyoblast injury. Concomitant treatment with Met-activating antibodies or HGF prevented apoptosis and autophagy. Pro-autophagic Redd1, Bnip3 and phospho-AMPK proteins, which are known to promote autophagy through inactivation of the mTOR pathway, were induced by CoCl2. Mechanistically, Met agonist antibodies or HGF prevented the inhibition of mTOR and reduced the flux of autophagosome formation. Accordingly, their anti-autophagic function was completely blunted by Temsirolimus, a specific mTOR inhibitor. Targeted Met activation was successful also in the setting of low oxygen conditions, in which Met agonist antibodies or HGF demonstrated anti-apoptotic and anti-autophagic effects. Activation of the Met pathway is thus a promising novel therapeutic tool for ischaemic injury.

  18. Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

    PubMed Central

    Perroy, Julie; Walwyn, Wendy M.; Smith, Monique L.; Vicente-Sanchez, Ana; Segura, Laura; Bana, Alia; Kieffer, Brigitte L.; Evans, Christopher J.

    2016-01-01

    Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. SIGNIFICANCE STATEMENT Agonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560

  19. Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists.

    PubMed

    Ida, Yoshihiro; Nemoto, Toru; Hirayama, Shigeto; Fujii, Hideaki; Osa, Yumiko; Imai, Masayuki; Nakamura, Takashi; Kanemasa, Toshiyuki; Kato, Akira; Nagase, Hiroshi

    2012-01-15

    The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the δ opioid receptor. In the course of examining the structure-activity relationship of SN-28 derivatives, the derivatives with the 4-hydroxy group (SN-24, 26, 27) showed higher selectivities for the δ receptor over the μ receptor than the corresponding SN-28 derivatives with the 3-hydroxy group (SN-11, 23, 28). Derivatives with the 4-hydroxy group showed potent agonist activities for the δ receptor in the [(35)S]GTPγS binding assay. Although the 17-cyclopropylmethyl derivative (SN-11) with a 3-hydroxy group showed the lowest selectivity for the δ receptor among the morphinan derivatives, the agonist activity toward the δ receptor was the most potent for candidates with the 3-hydroxy group.

  20. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

    SciTech Connect

    Thompson, Scott K.; Washburn, David G.; Frazee, James S.; Madauss, Kevin P.; Hoang, Tram H.; Lapinski, Leahann; Grygielko, Eugene T.; Glace, Lindsay E.; Trizna, Walter; Williams, Shawn P.; Duraiswami, Chaya; Bray, Jeffrey D.; Laping, Nicholas J.

    2010-09-03

    Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

  1. Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects.

    PubMed

    Dvorak, Curt A; Liu, Changlu; Shelton, Jonathan; Kuei, Chester; Sutton, Steven W; Lovenberg, Timothy W; Carruthers, Nicholas I

    2012-08-09

    Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity.

  2. The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.

    PubMed

    Westaway, Susan M; Brown, Samantha L; Conway, Elizabeth; Heightman, Tom D; Johnson, Christopher N; Lapsley, Kate; Macdonald, Gregor J; MacPherson, David T; Mitchell, Darren J; Myatt, James W; Seal, Jon T; Stanway, Steven J; Stemp, Geoffrey; Thompson, Mervyn; Celestini, Paolo; Colombo, Andrea; Consonni, Alessandra; Gagliardi, Stefania; Riccaboni, Mauro; Ronzoni, Silvano; Briggs, Michael A; Matthews, Kim L; Stevens, Alexander J; Bolton, Victoria J; Boyfield, Izzy; Jarvie, Emma M; Stratton, Sharon C; Sanger, Gareth J

    2008-12-15

    Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.

  3. Peroxisome proliferator-activated receptoragonists attenuate biofilm formation by Pseudomonas aeruginosa.

    PubMed

    Bedi, Brahmchetna; Maurice, Nicholas M; Ciavatta, Vincent T; Lynn, K Sabrina; Yuan, Zhihong; Molina, Samuel A; Joo, Myungsoo; Tyor, William R; Goldberg, Joanna B; Koval, Michael; Hart, C Michael; Sadikot, Ruxana T

    2017-08-01

    Pseudomonas aeruginosa is a significant contributor to recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein P. aeruginosa secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)-l-homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence via interbacterial communication. Strategies that strengthen the host's ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor γ (PPARγ) agonists are potent immunostimulators that play a pivotal role in host response to virulent P. aeruginosa Here, we show that QS genes in P. aeruginosa (strain PAO1) and 3O-C12-HSL attenuate PPARγ expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPARγ agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPARγ agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPARγ agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated via paraoxonase-2. These findings elucidate a novel role for

  4. The partial 5-HT1A receptor agonist buspirone enhances neurogenesis in the opossum (Monodelphis domestica).

    PubMed

    Grabiec, Marta; Turlejski, Kris; Djavadian, Rouzanna L

    2009-06-01

    We demonstrate for the first time that neurogenesis in the adult Monodelphis opossum has a typical mammalian pattern and occurs only in the dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles. In these two brain regions neurogenesis is present throughout the lifespan, although its rate is reduced by half in the old age. Treatment with buspirone, a partial 5-HT1A receptor agonist which is used in human clinic as an anxiolytic agent, boosts proliferation in the SVZ and DG in both adult and aged opossums. The neuronal phenotype dominates among newly generated cells in both non-treated and buspirone-treated opossums. We suggest that if functional importance of adult neurogenesis is in improving olfactory discrimination and generation of hippocampus-dependent memory, both spatial and emotional, then administration of drugs increasing the rate of neurogenesis via activation of 5-HT1A receptors may be a valuable aid in combating problems of the advanced age.

  5. Cognitive impairments induced by triazolam in healthy volunteers: antagonism by a partial inverse agonist of benzodiazepine receptor.

    PubMed

    Warot, D; Danjou, P; Douillet, P; Keane, P; Puech, A J

    1994-01-01

    Pharmacological studies revealed that SR 25776 possesses marked stimulant activity characteristic of a partial inverse agonist of benzodiazepine receptor. The effects of SR 25776 500 mg alone and in combination with triazolam 0.25 mg on psychomotor performance and memory were assessed in 8 healthy consenting male volunteers in a double-blind placebo controlled trial. Treatment effects were monitored before and two and half hours following oral medication. The present study suggest that at the studied dose SR 25776 may incompletely antagonize the sedative and amnesic effects of a benzodiazepine agonist without producing marked effects of its own.

  6. Effects of an intrathecally administered benzodiazepine receptor agonist, antagonist and inverse agonist on morphine-induced inhibition of a spinal nociceptive reflex.

    PubMed Central

    Moreau, J. L.; Pieri, L.

    1988-01-01

    1. The effects of an intrathecally administered benzodiazepine receptor (BZR) agonist (midazolam, up to 50 micrograms), antagonist (flumazenil, Ro 15-1788, 5 micrograms) and inverse agonist (Ro 19-4603, 15 micrograms) on nociception and on morphine-induced antinociception were studied in rats. 2. By themselves, none of these compounds significantly altered pain threshold. 3. The BZR agonist midazolam enhanced the morphine-induced antinociceptive effect whereas the antagonist flumazenil did not alter it. In contrast, the BZR inverse agonist Ro 19-4603 decreased the morphine-induced antinociceptive effect. 4. Naloxone (1 mg kg-1 i.p.) completely reversed all these effects. 5. These results demonstrate that BZR agonists and inverse agonists are able to affect, by allosteric up- or down-modulation of gamma-aminobutyric acidA (GABAA)-receptors, the transmission of nociceptive information at the spinal cord level, when this transmission is depressed by mu-opioid receptor activation. PMID:2898960

  7. CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity.

    PubMed

    Baillie, Gemma L; Horswill, James G; Anavi-Goffer, Sharon; Reggio, Patricia H; Bolognini, Daniele; Abood, Mary E; McAllister, Sean; Strange, Phillip G; Stephens, Gary J; Pertwee, Roger G; Ross, Ruth A

    2013-02-01

    We have previously identified allosteric modulators of the cannabinoid CB(1) receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB(1) receptor agonist [(3)H]CP55940 but producing a decrease in CB(1) receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB(1) receptor activation. We assessed the effect of these compounds on CB(1) receptor agonist-induced [(35)S]GTPγS binding, inhibition, and stimulation of forskolin-stimulated cAMP production, phosphorylation of extracellular signal-regulated kinases (ERK), and β-arrestin recruitment. We also investigated the effect of these allosteric modulators on CB(1) agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signaling as compared with WIN55212 and having little effect on [(3)H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding, simulation (Gα(s)-mediated), and inhibition (Gα(i)-mediated) of cAMP production and β-arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphorylation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic-binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high-affinity CB(1) agonist binding sites. The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway.

  8. Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease.

    PubMed

    Yahiaoui, Samir; Hamidouche, Katia; Ballandonne, Céline; Davis, Audrey; de Oliveira Santos, Jana Sopkova; Freret, Thomas; Boulouard, Michel; Rochais, Christophe; Dallemagne, Patrick

    2016-10-04

    5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Nicotinic receptor agonists as neuroprotective/neurotrophic drugs. Progress in molecular mechanisms.

    PubMed

    Mudo, G; Belluardo, N; Fuxe, K

    2007-01-01

    In the present work we reviewed recent advances concerning neuroprotective/neurotrophic effects of acute or chronic nicotine exposure, and the signalling pathways mediating these effects, including mechanisms implicated in nicotine addiction and nAChR desensitization. Experimental and clinical data largely indicate long-lasting effects of nicotine and nicotinic agonists that imply a neuroprotective/neurotrophic role of nAChR activation, involving mainly alpha7 and alpha4beta2 nAChR subtypes, as evidenced using selective nAChR agonists. Compounds interacting with neuronal nAChRs have the potential to be neuroprotective and treatment with nAChR agonists elicits long-lasting neurotrophic effects, e.g. improvement of cognitive performance in a variety of behavioural tests in rats, monkeys and humans. Nicotine addiction, which is mediated by interaction with nACh receptors, is believed to involve the modification of signalling cascades that modulate synaptic plasticity and gene expression. Desensitization, in addition to protecting cells from uncontrolled excitation, is recently considered as a form of signal plasticity. nAChR can generate these longe-lasting effects by elaboration of complex intracellular signals that mediate medium to long-term events crucial for neuronal maintenance, survival and regeneration. Although a comprehensive survey of the gene-based molecular mechanisms that underlie nicotine effects has yet not been performed a growing amount of data is beginning to improve our understanding of signalling mechanisms that lead to neurotrophic/neuroprotective responses. Evidence for an involvement of the fibroblast growth factor-2 gene in nAChR mechanisms mediating neuronal survival, trophism and plasticity has been obtained. However, more work is needed to establish the mechanisms involved in the effects of nicotinic receptor subtype activation from cognition-enhancing and neurotrophic effects to smoking behaviour and to determine more precisely the

  10. Pharmacological characterization of a highly selective and potent partial agonist of the MT₂ melatonin receptor.

    PubMed

    Sakurai, Taku; Koike, Tatsuki; Nakayama, Masaharu

    2014-01-01

    The MT₂ melatonin receptor is a potential target for treating circadian rhythm sleep disorders. This study aims to characterize the recently identified MT₂ melatonin receptor agonist. The pharmacological properties of the MT₂ melatonin receptor-selective agonist as exemplified by compound 1 [N-(2-[7-benzyl-1,6-dihydro-2H-indeno(5,4-b)furan-8-yl]ethyl)acetamide] were evaluated by use of cell-free binding and cell-based functional assays. Competition binding assays using 2-[(125)I]iodomelatonin revealed rapid, reversible, and high-affinity binding of compound 1 to human, mouse, and rat MT₂ melatonin receptors. cAMP, ERK1/2, and PathHunter β-arrestin recruitment assays revealed partial agonist activities. However, compound 1 induced a more intense internalization of human MT₂ melatonin receptor than melatonin. Based on studies using structurally related analogs of compound 1, we further demonstrated that the extent of internalization is independent of the intrinsic efficacy of agonists. These findings provide novel insights into the relationship between intrinsic agonist efficacy and agonist-induced internalization and demonstrate that compound 1 could serve as a pharmacological tool for future studies to elucidate the detailed molecular mechanism of MT₂ receptor internalization. © 2014 S. Karger AG, Basel.

  11. Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity.

    PubMed

    Micheli, Laura; Di Cesare Mannelli, Lorenzo; Rizzi, Anna; Guerrini, Remo; Trapella, Claudio; Calò, Girolamo; Ghelardini, Carla

    2015-11-05

    Oxaliplatin and paclitaxel are considered central components in the treatment of colorectal and breast cancer, respectively. The development of neuropathy during chronic treatment represents the major dose-limiting side effect that leads to discontinuation or interruption of therapies. The management of neuropathy is a challenge to individuate innovative therapeutic strategies based on new targets and correct routes of administration. We evaluated the hypersensitivity reliever effect of different opioid receptor agonists in rat models of oxaliplatin and paclitaxel-induced neuropathy. Compounds were spinally infused by intrathecal catheter. In oxaliplatin-treated rats, 0.3 nmol morphine induced the reversion of the mechanical hypersensitivity (Paw-pressure test), nociceptin/orphanin FQ (N/OFQ; 0.3-3 nmol) significantly increased the pain threshold without reaching the values of the control animals. The N/OFQ peptide (NOP) receptor full agonist UFP-112 reverted pain threshold alterations at lower dosage (0.1 nmol) vs morphine and N/OFQ, the partial agonist UFP-113 (0.1-1 nmol) was similar to N/OFQ. The higher efficacy of morphine vs N/OFQ was highlighted also in paclitaxel-treated rats. The mechanical hypersensitivity was fully reverted by 0.1 nmol UFP-112 and UFP-113. In conclusion, intrathecal μ opioid peptide (MOP) and NOP receptor agonists relieved chemotherapy-induced neuropathic pain. The synthetic peptides showed valuable potency and efficacy suggesting the NOP system as an exploitable target.

  12. Use-dependent inhibition of P2X3 receptors by nanomolar agonist.

    PubMed

    Pratt, Emily B; Brink, Thaddeus S; Bergson, Pamela; Voigt, Mark M; Cook, Sean P

    2005-08-10

    P2X3 receptors desensitize within 100 ms of channel activation, yet recovery from desensitization requires several minutes. The molecular basis for this slow rate of recovery is unknown. We designed experiments to test the hypothesis that this slow recovery is attributable to the high affinity (< 1 nM) of desensitized P2X3 receptors for agonist. We found that agonist binding to the desensitized state provided a mechanism for potent inhibition of P2X3 current. Sustained applications of 0.5 nM ATP inhibited > 50% of current to repetitive applications of P2X3 agonist. Inhibition occurred at 1000-fold lower agonist concentrations than required for channel activation and showed strong use dependence. No inhibition occurred without previous activation and desensitization. Our data are consistent with a model whereby inhibition of P2X3 by nanomolar [agonist] occurs by the rebinding of agonist to desensitized channels before recovery from desensitization. For several ATP analogs, the concentration required to inhibit P2X3 current inversely correlated with the rate of recovery from desensitization. This indicates that the affinity of the desensitized state and recovery rate primarily depend on the rate of agonist unbinding. Consistent with this hypothesis, unbinding of [32P]ATP from desensitized P2X3 receptors mirrored the rate of recovery from desensitization. As expected, disruption of agonist binding by site-directed mutagenesis increased the IC50 for inhibition and increased the rate of recovery.

  13. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

  14. Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats.

    PubMed

    Li, Su-Min; Collins, Gregory T; Paul, Noel M; Grundt, Peter; Newman, Amy H; Xu, Ming; Grandy, David K; Woods, James H; Katz, Jonathan L

    2010-05-01

    Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.

  15. Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide

    PubMed Central

    White, William B.; Myers, Martin G.; Jordan, Robert; Lucas, Johna

    2017-01-01

    Background: Melanocortin receptor agonists that bind to the melanocortin receptor 4 may cause increases in blood pressure (BP). Bremelanotide is an on-demand, subcutaneous melanocortin-receptor agonist that binds to the melanocortin receptor 4 and is being developed for the treatment of female sexual dysfunction. Methods: We studied the effects of bremelanotide administration on ambulatory BP and heart rate (HR), in a randomized, double-blind, placebo-controlled, and parallel-arm trial of three doses of bremelanotide (0.75, 1.25, and 1.75 mg) in 397 premenopausal women with female sexual dysfunction with normotension or controlled hypertension. Pharmacokinetic exposure was assessed in conjunction with ambulatory BP measurements. Results: Increases in ambulatory SBP relative to placebo of 2.4 and 3.0 mmHg (1.25 mg; P values: 0.029 and 0.076) and 3.1 and 3.2 mmHg (1.75 mg; P values: 0.006 and 0.027), respectively, occurred following two doses, separated by 24 h at the 0 to 4-h postdose interval; peak increases typically lasted less than 15 min. Similar increases in the DBP were observed. Increases in BP were accompanied by reductions in HR during the 0–4-h interval for the 1.75-mg dose (−4.6 to −4.7 bpm; P < 0.001). Twenty-six participants discontinued after randomization due to prespecified increases in BP but the proportions were similar among the four treatment groups. Conclusion: These data show that ambulatory monitoring was a useful methodology to detect small, transient increases in ambulatory BP accompanied by reductions in HR following bremelanotide. Results of this trial led to appropriate in-clinic BP monitoring during the larger clinical development trials of this agent for female sexual dysfunction. PMID:27977473

  16. δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice

    PubMed Central

    Pradhan, Amynah A; Smith, Monique L; Zyuzin, Jekaterina; Charles, Andrew

    2014-01-01

    Background and Purpose Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. Experimental Approach Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. Key Results NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that δ-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. Conclusions and Implications These data show that δ-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ-opioid receptors are a promising therapeutic target for this disorder. PMID:24467301

  17. The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats.

    PubMed

    Wirtshafter, David; Osborn, Catherine V

    2005-12-28

    The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a neces