CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2008
Mitsu Onoma
SUMMARY 1The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active motilin receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200,300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs comapred with normal dogs at both time points. 4Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs comapred with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis. [source]

ROSIGLITAZONE, AN AGONIST OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, PREVENTS CONTRALATERAL TESTICULAR ISCHAEMIA,REPERFUSION INJURY IN PREPUBERTAL RATS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2007
Mustafa Inan
SUMMARY 1Rosiglitazone plays a positive role in the reparation of ischaemia,reperfusion (I/R) injury in different tissues. Thus, we examined its biochemical and histological effects on the contralateral testes to determine whether exogenous rosiglitazone affords any protection against testicular damage. 2Forty-eight prepubertal male Wistar-Albino rats were divided into six groups. Testicular torsion was created by rotating the right testis 720° in a clockwise direction for 5 h in all groups except group I, which was the sham-control group. In group II, bilateral orchiectomy was performed following the torsion period. After detorsion both testes were removed in the fifth hour in group III and on the seventh day in group IV. In group V, one-shot rosiglitazone (4 mg/kg) was administered 40 min before detorsion and both testes were removed following the torsion period. In group VI, rosiglitazone was administered (4 mg/kg) 40 min before detorsion and for 7 days, and then both testes were harvested. The tissue levels of malondialdehyde (MDA) were measured and mean testicular biopsy score (MTBS) and mean seminiferous tubule diameter (MSTD) were examined. Immunoexpression of endothelial nitric oxide synthase (eNOS) in testes tissues was investigated by immunohistochemical studies. 3In the contralateral testis, the MTBS and MSTD values of group VI were significantly higher than those in group IV. Immunohistochemically, mild eNOS immunostaining was present in the germ cells of the contralateral testes in group IV after I/R. In group VI, intense eNOS immunoreactivity was seen in the contralateral testes. 4Rosiglitazone reduces contralateral testicular damage formed after unilateral testicular torsion and alleviates the oxidative events. [source]

WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS IN VULNERABLE INDIVIDUALS

ADDICTION, Issue 10 2010
SUSANNA EVERY-PALMER
No abstract is available for this article. [source]

DANGERS OF BANNING SPICE AND THE SYNTHETIC CANNABINOID AGONISTS

ADDICTION, Issue 2 2010
RICHARD HAMMERSLEY
No abstract is available for this article. [source]

Tocolytic Effects of a Long-acting ,2 -Adrenoceptor Agonist, Formoterol, in Rats

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000
NORIHIRO SHINKAI
We have assessed the tocolytic activity of formoterol, a novel long-acting and potent ,2 -adrenoceptor agonist, through its production of cyclic adenosine monophosphate, in comparison with ritodrine, a ,2 -adrenoceptor agonist used clinically to counter premature delivery. Formoterol and ritodrine inhibited the amplitude and frequency of rat uterine contraction, with IC50 values of 3.8 times 10,10 and 4.7 times 10,7 M, respectively. Intravenous administration of formoterol or ritodrine caused inhibition of uterine motility and increased heart rate in a dose-dependent manner. Inhibition of uterine motility by oral administration of formoterol (0.3 and 1 mg kg,1) continued for at least 60 min, whereas that with ritodrine (100 mg kg,1) persisted for 15 min with rapid recovery thereafter in pregnant rats. The ,-adrenoceptor binding of [125I]iodopindolol to the myometrium of pregnant rats was competitive with formoterol and ritodrine, with Ki values of 0.04 and 6.10 nM, respectively. Formoterol (10,6 , 10,4 M) and ritodrine (10,6 , 10,4 M) increased the level of cyclic adenosine monophosphate in lymphocytes in a dose-dependent manner. The results suggested that formoterol caused relaxation of uterine motility through production of cyclic adenosine monophosphate. Thus, formoterol may be useful as a treatment to counter premature delivery. [source]

Attenuation of the Stimulant Response to Ethanol is Associated with Enhanced Ataxia for a GABAA, but not a GABAB, Receptor Agonist

ALCOHOLISM, Issue 1 2009
Sarah E. Holstein
Background:, The ,-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods:, In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results:, NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions:, These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders. [source]

2-Phenylmelatonin: A Partial Agonist at Enteric Melatonin Receptors

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2000
Maria Grazia Santagostino-Barbone
The effect of the melatonin receptor ligand, 2-phenylmelatonin, has been assessed in isolated strips of the guinea-pig proximal colon. 2-Phenylmelatonin (0.01 nM-1 ,M) caused a concentration-dependent contractile response. The potency value (,log EC50) was 9.3±1.0. The maximum effect was 25±4% of that elicited by the maximally effective concentration (0.3 ,M) of 5-HT and 43±3% of that by the maximally effective concentration (10 ,M) of melatonin. When used as an antagonist, 2-phenylmelatonin (0.01 nM and 0.1 nM) concentration-dependently inhibited melatonin-induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2-phenylmelatonin concentrations failed to antagonize melatonin-induced response. Prazosin (0.3 ,M), a selective antagonist of melatonin MT3 sites, antagonized melatonin-induced contractions to an extent similar to that induced by 0.01 nM 2-phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 ,M prazosin and 0.01 nM 2-phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2-Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin-induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist. [source]

Photocaged Agonist for an Analogue-Specific form of the Vitamin D Receptor

CHEMBIOCHEM, Issue 7 2007
John B. Biggins Dr.
Abstract Nuclear hormone receptors (NHRs) represent a diverse class of ligand-dependent transcriptional regulators. NHRs that have been rendered functionally inactive due to mutations that abrogate proper ligand binding can often be rescued by appropriately designed hormone analogues. The analogue-specific receptor,ligand pairs provide an ideal platform from which to develop new chemogenomic tools for the spatial and temporal control of gene expression. Here, we describe the synthesis and in vitro assessment of a photocaged VDR agonist specific to a mutant NHR that is associated with vitamin D-resistant rickets. The results provide insight into the utility of the agonist as a potential tool for photoinduced gene patterning. [source]

Delta2 -Specific Opioid Receptor Agonist and Hibernating Woodchuck Plasma Fraction Provide Ischemic Neuroprotection

ACADEMIC EMERGENCY MEDICINE, Issue 3 2008
Meera Govindaswami PhD
Abstract Objectives:, The authors present evidence that the , opioid receptor agonist Deltorphin-Dvariant (Delt-Dvar) and hibernating woodchuck plasma (HWP), but not summer-active woodchuck plasma (SAWP), can provide significant neuroprotection from focal ischemia in mice by a mechanism that relies in part on reducing nitric oxide (NO) release in ischemic tissue. Methods:, Cerebral ischemia was produced in wild-type and NO synthase,deficient (NOS,/,) mice by transient, 1-hour middle cerebral artery occlusion (MCAO). Behavioral deficits were determined at 22 hours and infarct volume was assessed at 24 hours after MCAO. Mice were treated with saline or Delt-Dvar at 2.0 and 4.0 mg/kg, or 200 ,L of HWP or SAWP. NOS,/, mice were treated with either saline or Delt-Dvar at 4.0 mg/kg. NO release was determined using an N9 microglial cell line pretreated with ,- or ,-specific opioids and HWP or SAWP prior to activation with lipopolysaccharide and interferon-,. Nitrate in the medium was measured as an indicator of NO production. Results:, Infusion of Delt-Dvar or HWP (but not SAWP) decreased infarct volume and improved behavioral deficits following 1 hour of MCAO and 24 hours of reperfusion. In NOS,/, mice, endothelial NOS+/+ is required to provide Delt-Dvar,induced neuroprotection. Delt-Dvar and HWP dose-dependently decreased NO release in cell culture, while SAWP and other ,- and ,-specific opioids did not. Conclusions:, Delt-Dvar and HWP, but not SAWP, are effective neuroprotectant agents in a mouse model of transient MCAO. In cell culture, the mechanism of this ischemic neuroprotection may rely in part on their ability to block NO release. [source]

ChemInform Abstract: Design and Synthesis of a Functionally Selective D3 Agonist and Its in vivo Delivery via the Intranasal Route.

CHEMINFORM, Issue 11 2008
Julian Blagg
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

A Facile One-Pot Preparation of Alkyl Aminoaryl Sulfides for the Synthesis of GW7647 as an Agonist of Peroxisome Proliferator-Activated Receptor ,.

CHEMINFORM, Issue 49 2006
Jungyeob Ham
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]

Synthesis of 15R-PGD2: A Potential DP2 Receptor Agonist.

CHEMINFORM, Issue 31 2005
Seongjin Kim
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Construction of Arene-Fused-Piperidine Motifs by Asymmetric Addition of 2-Trityloxymethylaryllithiums to Nitroalkenes: The Asymmetric Synthesis of a Dopamine D1 Full Agonist, A-86929.

CHEMINFORM, Issue 23 2004
Mitsuaki Yamashita
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Application of the Lewis Acid,Lewis Base Bifunctional Asymmetric Catalysts to Pharmaceutical Syntheses: Stereoselective Chiral Building Block Syntheses of Human Immunodeficiency Virus (HIV) Protease Inhibitor and ,3 -Adrenergic Receptor Agonist.

CHEMINFORM, Issue 44 2003
Hiroyuki Nogami
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

ChemInform Abstract: Efficient Asymmetric Synthesis of (S)-2-Ethylphenylpropanoic Acid Derivative, a Selective Agonist for Human Peroxisome Proliferator-Activated Receptor Alpha.

CHEMINFORM, Issue 49 2002
Masahiro Nomura
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

The Predicted 3D Structures of the Human M1 Muscarinic Acetylcholine Receptor with Agonist or Antagonist Bound

CHEMMEDCHEM, Issue 8 2006
Joyce Yao-chun Peng
Abstract The muscarinic acetylcholine G-protein-coupled receptors are implicated in diseases ranging from cognitive dysfunctions to smooth-muscle disorders. To provide a structural basis for drug design, we used the MembStruk computational method to predict the 3D structure of the human M1 muscarinic receptor. We validated this structure by using the HierDock method to predict the binding sites for three agonists and four antagonists. The intermolecular ligand,receptor contacts at the predicted binding sites agree well with deductions from available mutagenesis experiments, and the calculated relative binding energies correlate with measured binding affinities. The predicted binding site of all four antagonists is located between transmembrane (TM) helices,3, 4, 5, 6, and 7, whereas the three agonists prefer a site involving residues from TM3, TM6, and TM7. We find that Trp,157(4) contributes directly to antagonist binding, whereas Pro,159(4) provides an indirect conformational switch to position Trp,157(4) in the binding site (the number in parentheses indicates the TM helix). This explains the large decrease in ligand binding affinity and signaling efficacy by mutations of Trp,157(4) and Pro,159(4) not previously explained by homology models. We also found that Asp,105(3) and aromatic residues Tyr,381(6), Tyr,404(7), and Tyr,408(7) are critical for binding the quaternary ammonium head group of the ligand through cation,, interactions. For ligands with a charged tertiary amine head group, we suggest that proton transfer from the ligand to Asp,105(3) occurs upon binding. Furthermore, we found that an extensive aromatic network involving Tyr,106(3), Trp,157(4), Phe,197(5), Trp,378(6), and Tyr,381(6) is important in stabilizing antagonist binding. For antagonists with two terminal phenyl rings, this aromatic network extends to Trp,164(4), Tyr,179(extracellular loop,2), and Phe,390(6) located at the extracellular end of the TMs. We find that Asn,382(6) forms hydrogen bonds with selected antagonists. Tyr381(6) and Ser,109(3) form hydrogen bonds with the ester moiety of acetylcholine, which binds in the gauche conformation. [source]

Both the Peroxisome Proliferator-Activated Receptor , Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL-Derived Cholesterol

CLINICAL AND TRANSLATIONAL SCIENCE, Issue 2 2009
François Briand Ph.D.
Abstract Peroxisome proliferator-activated receptor , (PPAR,) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage-to-feces reverse cholesterol transport (RCT). To test whether PPARÔ activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol-loaded/3H-cholesterol-labeled macrophages injected intraperitoneally. PPARÔ agonist GW0742 (10 mg/kg per day) did not change 3H-tracer plasma appearance, but increased fecal 3H-free sterols excretion by 103% (p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with 3H-cholesteryl ether or 3H-cholesteryl oleate was also measured. While 3H-cholesteryl ether tissue uptake was unchanged, the 3H-tracer recovered in fecal free sterol fraction after 3H-cholesteryl oleate injection increased by 88% with GW0742 (p < 0.0005). This was associated with a lower Niemann-Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine (p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2-fold increase in fecal free sterol excretion after labeled macrophages or HDL injection. In conclusion, PPARÔ activation enhances excretion of macrophage or HDL-derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe. [source]

Design of Cyclopentaisoxazoline Amino Acids as Conformationally Constrained Agonists at Glutamate Receptors

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2003
Paola Conti
Abstract We have prepared four isomeric 3-hydroxycyclopentaisoxazoline amino acids 12,15, which represent analogues of glutamic acid having restricted conformations, through a strategy based on the 1,3-dipolar cycloaddition of bromonitrile oxide to a suitably protected 1-aminocyclopent-2-enecarboxylic acid. These target compounds proved to be inactive when assayed at ionotropic and metabotropic glutamate receptors, except for 12 which is an agonist primarily at mGluR5 (EC50 = 79 ,M), but is less active at mGluR2 and only marginally active at mGluR1. The biological data are accounted for through comparison of the conformational profiles of the test compounds with that of reference agonists, i.e., N -methyl- D -aspartate (NMDA, 2), and 1-aminocyclopentane-1,3-dicarboxylic acids [trans -ACPD, 10; cis -ACPD, 11]. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source]

Agonists of proteinase-activated receptor-2 affect transendothelial migration and apoptosis of human neutrophils

EXPERIMENTAL DERMATOLOGY, Issue 10 2007
Victoria M. Shpacovitch
Abstract:, Skin is the first barrier preventing microorganism invasion in host. Wounds destroy this defense barrier and, without an appropriate care, may lead to sepsis. Neutrophil activation and immigration plays an important role at the inflammatory stage of wound healing. Neutrophils are known to express proteinase-activated receptors (PARs), which can be activated by serine proteases, also by enzymes involved in wound healing. We previously reported that PAR2 agonists up-regulate cell adhesion molecule expression and cytokine production by human neutrophils. Here, we demonstrate that PAR2 agonists (serine proteases as well as synthetic peptides) reduce transendothelial migration of neutrophils and prolong their life in vitro. Synthetic PAR2 agonist also enhanced protective interferon (IFN),-induced Fc,RI expression at neutrophil cell surface. Of note, IFN, is a cytokine, which was used in clinical trials to reactivate human neutrophil functions during sepsis. Moreover, we observed a significant increase of PAR2 expression on cell surface of neutrophils from septic patients as compared with healthy volunteers. Together, our results indicate that PAR2 may be involved in the pathophysiology of neutrophil-endothelial interactions during wound healing or later during sepsis in humans, potentially by affecting neutrophil apoptosis, transendothelial migration and Fc, receptor-mediated phagocytosis. [source]

5-HT1B/1D Agonists, Oral Contraceptives, and Ischemic Colitis,A Response

HEADACHE, Issue 6 2006
James A. Charles MD
No abstract is available for this article. [source]

The 14-Alkyl- and 14-Alkenyl-5, -methylindolomorphinan Series Provide , -Selective Partial Opioid Agonists

HELVETICA CHIMICA ACTA, Issue 3 2003
Peter Grundt
A series of 14, -alkyl- and 14, -alkenyl-5, -methylindolomorphinans was synthesized and evaluated in opioid binding and functional assays. While being relatively nonselective in binding assays, the 14-cinnamyl and 14-isopentyl members showed selective opioid , -receptor partial agonist activity in [35S]GTP,S assays. [source]

COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells

HEPATOLOGY, Issue 3 2002
Ugochukwu C. Nzeako
Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptor,mediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-,, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells. [source]

Maintaining Cell Sensitivity to G-Protein Coupled Receptor Agonists: Neurotensin and the Role of Receptor Gene Activation

JOURNAL OF NEUROENDOCRINOLOGY, Issue 5 2001
F. Souazé
Abstract In the last few years, a number of studies have brought new insights into the fundamental mechanisms of cell desensitization and internalization of G-protein coupled receptors. Such studies have demonstrated that cells remain desensitized from a few minutes to several hours, after exposure to high concentrations of agonist. However, in vivo, agonists such as hormones are always present, even in small amounts, and such long desensitization is not conceivable, since constant stimulation of cells is required for physiological responses. Under such circumstances, cells would require a means to permanently maintain sensitivity to various internal or external stimuli. In the present review, we have taken as an example the expression of the high affinity neurotensin receptor, a seven transmembrane G-protein coupled receptor, upon prolonged exposure to its agonist, and observed that cells remained sensitive only if the receptor gene was activated by the agonist. Consequently, new receptors were synthesized, and either delivered to the cell surface or accumulated in submembrane pools. This regulation takes place only after prolonged and intense agonist stimulation. Under these conditions, it is proposed that receptor turnover is accelerated in proportion to the agonist concentration in order to allow the cells to produce an adapted cellular response to external stimuli. Such mechanisms thus play a key role in cell sensitivity to hormones. [source]

,2 -Agonists as analgesic agents

MEDICINAL RESEARCH REVIEWS, Issue 2 2009
Maria Paola Giovannoni
Abstract It is well known that norepinephrine is involved in the control of pain by modulating pain-related responses through various pathways. ,2 -Adrenergic agonists have a well-established analgesic profile and, in the recent years, have found a wider application, in particular as adjunct to anesthetics and analgesics in perioperative settings. This review analyzes the ,2 -agonists currently in clinical use, starting from the prototype Clonidine, as well as the most promising and studied molecules. In addition, an overview of the imidazoles, imidazolines, and hydroxyethyl-thioureas derivatives published in both the open and patented literature is presented, providing chemical description and pharmacological data. Finally, the most commonly ,2 -agonists used in veterinary medicine are described. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 2, 339,368, 2009 [source]

Novel Pirinixic Acids as PPAR, Preferential Dual PPAR,/, Agonists

MOLECULAR INFORMATICS, Issue 5 2009
Heiko Zettl
Abstract Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that ,-alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR, and PPAR,. Taking ,-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPAR, activity but further increased PPAR, activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR, ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantio-selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation. [source]

Oral administration of a centrally acting ghrelin receptor agonist to conscious rats triggers defecation

NEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2009
A. D. Shafton
Abstract, Agonists of ghrelin receptors that cross the blood,brain barrier, but not ghrelin itself, administered peripherally (intravenous or subcutaneous), cause defecation by acting on centres in the lumbo-sacral spinal cord. It is not established whether orally administered ghrelin receptor agonists can have this action. We tested GSK894281 for its effectiveness at the ghrelin receptor and its ability to cross the blood,brain barrier. GSK894281 was effective at the human and rat ghrelin receptors at 1,10 nmol L,1, but was >1000-fold less potent at the motilin receptor. It achieved a similar blood concentration by oral or intravenous administration. Oral bioavailability was 74% and brain : blood ratio at steady state was 0.7 : 1. GSK894281 administered orally (1,100 mg kg,1) caused a prompt, dose-related production of faecal pellets; at 10 mg kg,1 faecal output was four times greater than after carrier. The output was the greatest in the first half hour and subsided over the next 90 min. At an oral dose of 10 mg kg,1, the compound was effective on eight successive days. Faecal output was, on average, increased threefold over control in the 2 h after administration on each of the 8 days. This dose also significantly increased food consumption. Rats showed no adverse behavioural effects to the drug on a single application, but at the end of a week of administration they avoided the gavaging pipette. Oral administration of ghrelin receptor agonists that enter the central nervous system could possibly be used to relieve acute cases of constipation or to clear the bowel for colonoscopy. [source]

Peroxisome proliferator-activated receptor gamma in human prostate carcinoma

PATHOLOGY INTERNATIONAL, Issue 5 2009
Yasuhiro Nakamura
Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily of transcription factors. Peroxisome proliferator-activated receptor gamma (PPAR,) plays an important role in the regulation of lipid homeostasis, adipogenesis, insulin resistance, and development of various organs. Agonists of PPAR, have been also reported to inhibit proliferation of prostate carcinoma cells as in other human malignancies, and these synthetic ligands have been used in differentiation-mediated therapy of various human carcinomas associated with high levels of PPAR,. The significance of PPAR, expression, however, was unknown in human prostate carcinoma tissues. The purpose of the present study was therefore to examine the immunolocalization of PPAR, in human prostate cancer tissues (40 cases) and correlate the findings with clinicopathological features of the patients in order to evaluate its possible biological significance. Twenty-nine patients were positive for PPAR, immunoreactivity (73%) and a significant inverse correlation was detected between PPAR, immunoreactivity, pT stage (P = 0.036), and serum concentration of prostate-specific antigen (P = 0.0004). In conclusion, PPAR, immunoreactivity is considered to be a new clinicopathological parameter of human prostate cancer. [source]

Parental knowledge and use of epinephrine auto-injector for children with food allergy

PEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 3 2006
G. Pouessel
Epinephrine should be prescribed for patients at risk of anaphylaxis. Our purpose was to determine the use of Anapen® prescribed for food-allergic children, to assess parental knowledge regarding Anapen, and to evaluate the arrangements for emergency kits and personalized care projects in everyday life. A prospective study was performed with a questionnaire sent to families with a food-allergic child previously prescribed Anapen. One hundred and fifty two families were contacted and finally 111 children included (median age 6.5 yrs). Main food allergens were peanuts (n = 89), egg (n = 39) and cow's milk (n = 10). The use of Anapen had been demonstrated to 90% of parents (by prescribing physician, 69%; pharmacist, 25%; general practitioner, 5%; nurse 1%), with a training device (76%) and/or written instructions (49%). When asked to list symptoms requiring injection, 48% of parents cited more than one response: breathing difficulties only (23%), or with angio-edema (41%), collapse or faintness (38%), anaphylactic shock (48%). Of 107 children attending school, 54% had a personalized care project, 72% an Anapen device, and 60% a complete emergency kit (epinephrine, inhaled , -agonist, corticosteroid, anti-H1 drug). , -Agonists were forgotten at school by 34 children (13 asthmatics). Anapen was used in one child for angio-edema and dyspnea after inadvertent ingestion of egg at home. In our population, epinephrine auto-injectors and emergency kits were insufficiently available at schools and in daily life. The use of auto-injectors was not adequately demonstrated. The prescription of epinephrine for food-allergic children at risk of anaphylaxis requires accurate diagnosis, educational programs, information, and follow up. [source]

Ultraviolet B Radiation of Human Skin Generates Platelet-activating Factor Receptor Agonists

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2010
Jared B. Travers
Ultraviolet B radiation (UVB) is a potent stimulator of epidermal cytokine production. In addition to cytokines, such as tumor necrosis factor-alpha (TNF-,), UVB generates bioactive lipids including platelet-activating factor (PAF). Our previous in vitro studies in keratinocytes or epithelial cell lines have demonstrated that UVB-mediated production of PAF agonists is due primarily to the pro-oxidative effects of this stimulant, resulting in the nonenzymatic production of modified phosphocholines (oxidized glycerophosphocholines). The current studies use human skin to assess whether UVB irradiation generates PAF-receptor agonists, and the role of oxidative stress in their production. These studies demonstrate that UVB irradiation of human skin results in PAF agonists, which are blocked by the antioxidant vitamin C and the epidermal growth factor receptor inhibitor PD168393. Inasmuch as UVB-generated PAF agonists have been implicated in animal model systems as being involved in photobiologic processes including systemic immunosuppression and cytokine (TNF-,) production, these studies indicate that this novel activity could be involved in human disease. [source]

Pharmacological and Functional Characterization of Novel EP and DP Receptor Agonists: DP1 Receptor Mediates Penile Erection in Multiple Species

THE JOURNAL OF SEXUAL MEDICINE, Issue 2 2008
Nadia Brugger PhD
ABSTRACT Introduction., Despite the widespread use of prostaglandin E1 as an efficacious treatment for male erectile dysfunction for more than two decades, research on prostanoid function in penile physiology has been limited. Aim., To characterize the pharmacological and physiological activity of novel subtype-selective EP and DP receptor agonists. Methods., 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. Main Outcome Measures., Receptor binding and signal transduction, smooth muscle contractile activity, erectile function. Results., 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 PGE1 (EC50 = 0.23 µM). 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 (EC50 =29 nM) was more effective in relaxing human cavernosal tissue than either PGE1, PGD2 (EC50 = 58 nM), or the DP agonist BW245C (EC50 =59 nM). In rabbit cavernosal tissue, PGE1 and PGD2 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. Conclusions., 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 stimulates pro-erectile responses in rat and rabbit. Thus, rabbits and rats can be useful models for investigating the physiological function of DP1 receptors. Brugger N, Kim NN, Araldi GL, Traish AM, and Palmer SS. Pharmacological and functional characterization of novel EP and DP receptor agonists: DP1 receptor mediates penile erection in multiple species. J Sex Med 2008;5:344,356. [source]