EVOLUTION, Issue 4 2010
Adam M. Siepielski
The raw material for evolution is variation. Consequently, identifying the factors that generate, maintain, and erode phenotypic and genetic variation in ecologically important traits within and among populations is important. Although persistent directional or stabilizing selection can deplete variation, spatial variation in conflicting directional selection can enhance variation. Here, we present evidence that phenotypic variation in limber pine (Pinus flexilis) cone structure is enhanced by conflicting selection pressures exerted by its mutualistic seed disperser (Clark's nutcracker Nucifraga columbiana) and an antagonistic seed predator (pine squirrel Tamiasciurus spp.). Phenotypic variation in cone structure was bimodal and about two times greater where both agents of selection co-occurred than where one (the seed predator) was absent. Within the region where both agents of selection co-occurred, bimodality in cone structure was pronounced where there appears to be a mosaic of habitats with some persistent habitats supporting only the seed disperser. These results indicate that conflicting selection stemming from spatial variation in community diversity can enhance phenotypic variation in ecologically important traits. [source]

EFFECT OF COMBINATION THERAPY (ANG II ANTAGONIST, VALSARTAN AND A CALCIUM CHANNEL BLOCKER) IN A HYPERTENSIVE MODEL OF DIABETIC NEPHROPATHY

NEPHROLOGY, Issue 3 2000
Allen Tj Davis Bj
[source]

A Highly Efficient Synthesis of a Naphthalenoid Histamine-3 Antagonist

ADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 11-12 2009
Yi-Yin Ku
Abstract A highly efficient synthesis of the potent and selective histamine-3 receptor antagonist 1A was accomplished in four chemical steps and a salt formation step in 36% overall yield from 6-bromo-2-naphthalenol 9. The key features are a regioselective Suzuki coupling protocol for selective vinylation of 12 with potassium vinyltrifluoroborate in high yield (92%) with excellent regioselectivity (90:2) and a base-catalyzed hydroamination reaction of 11 in an anti-Markovnikov fashion under mild reaction conditions. An optimized copper-catalyzed cross coupling reaction is used to incorporate the pyridazinone 4. [source]

Tissue Distribution, Autoradiography, and Metabolism of 4-(2,-Methoxyphenyl)-1-[2, -[N -2,-Pyridinyl)- p -[18F]Fluorobenzamido]ethyl]piperazine (p -[18F]MPPF), a New Serotonin 5-HT1A Antagonist for Positron Emission Tomography

JOURNAL OF NEUROCHEMISTRY, Issue 2 2000
An In Vivo Study in Rats
The in vivo behavior of 4-(2,-methoxyphenyl)-1-[2,-[N -(2,-pyridinyl)- p -[18F]fluorobenzamido]ethyl]-piperazine (p -[18F]MPPF), a new serotonin 5-HT1A antagonist, was studied in awake, freely moving rats. Biodistribution studies showed that the carbon-fluorine bond was stable in vivo, that this compound was able to cross the blood-brain barrier, and that a general diffusion equilibrium could account for the availability of the tracer. The great quantity of highly polar metabolites found in plasma did not contribute to the small amounts of metabolites found in hippocampus, frontal cortex, and cerebellum. Exvivo p -[18F]MPPF and in vitro 8-hydroxy-2-(di- n -[3H]propylamino)tetralin autoradiography were compared both qualitatively and quantitatively. Qualitative evaluation proved that the same brain regions were labeled and that the p -[18F]MPPF labeling is (a) in total agreement with the known distribution of 5-HT1A receptors in rats and (b) characterized by very low nonspecific binding. Quantitative comparison demonstrated that the in vivo labeling pattern obtained with p -[18F]MPPF cannot be explained by differences in regional blood flow, capillary density, or permeability. The 5-HT1A specificity of p -[18F]MPPF and binding reversibility were confirmed in vivo with displacement experiments. Thus, this compound can be used to evaluate parameters characterizing 5-HT1A binding sites in the brain. [source]

A Pilot Trial of the Alpha-1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence

ALCOHOLISM, Issue 2 2009
Tracy L. Simpson
Background:, Current medications for alcohol dependence (AD) show only modest efficacy. None target brain noradrenergic pathways. Theory and preclinical evidence suggest that noradrenergic circuits may be involved in alcohol reinforcement and relapse. We therefore tested the ,-1 adrenergic receptor antagonist, prazosin, as a pharmacotherapy for AD. Methods:, We randomized 24 participants with AD but without posttraumatic stress disorder to receive either prazosin or placebo in a 6-week, double-blind pilot study. Medication was titrated to a target dose of 4 mg QAM, 4 mg QPM, and 8 mg QHS by the end of week 2. Participants received 5 medical management treatment sessions. Participants were reminded 3 times each day via a text pager to take medications and to call a telephone monitoring system once daily to provide self-reports of alcohol consumption and craving, the primary outcome measures. Results were analyzed using mixed linear regression adjusted for drinking days per week at baseline and week number. Results:, Twenty of the 24 (83%) subjects completed. Among the completers, the prazosin group reported fewer drinking days per week than the placebo group during the final 3 weeks of the study. Since only 1 woman was randomized to placebo and only three women completed the trial, the following results focus on the 17 male completers. The prazosin group reported fewer drinking days per week and fewer drinks per week during the final 3 weeks of the study; average total number of drinking days for the placebo group 5.7 (SEM 1.9) versus 0.9 (SEM 0.5) for the prazosin group, and average total number of drinks 20.8 (SEM 6.5) for the placebo group versus 2.6 (SEM 1.3) for the prazosin group. Rates of adverse events were equivalent across conditions. Conclusions:, Prazosin holds promise as a pharmacologic treatment for AD and deserves further evaluation in a larger controlled trial. [source]

The ,1 -Adrenergic Receptor Antagonist, Prazosin, Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats

ALCOHOLISM, Issue 2 2009
Dennis D. Rasmussen
Background:, Preliminary evidence suggest that noradrenergic signaling may play a role in mediating alcohol drinking behavior in both humans and rats. Accordingly, we tested the hypothesis that blockade of ,1 -adrenergic receptors will suppress alcohol drinking in rats selectively bred for alcohol preference (P line). Methods:, Adult male P rats were given 24-hour access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were injected IP with the ,1 -adrenergic receptor antagonist, prazosin (0, 0.5, 1.0, 1.5, or 2.0 mg/kg body weight), once a day at 15 minutes prior to onset of the daily 2-hour 2-bottle choice, alcohol versus water, access period for 2 consecutive days and then 3 weeks later for 5 consecutive days. Results:, Prazosin significantly reduced (p < 0.01) alcohol intake during the initial 2 daily administrations, and this reduction of alcohol intake was maintained for 5 consecutive days by daily prazosin treatment in the subsequent more prolonged trial (p < 0.05). The prazosin-induced reduction of alcohol intake was not dependent upon drug-induced motor impairment since increases in water drinking (p < 0.05) were exhibited during the 2-hour access periods during both 2- and 5-day prazosin treatment. Conclusions:, The results indicate that the noradrenergic system plays a role in mediating alcohol drinking in rats of the P line and suggest that prazosin,a safe, well-characterized, and well-tolerated drug,may be an effective pharmacotherapeutic agent for the treatment of alcohol use disorders. [source]

Effects of the Glucocorticoid Antagonist, Mifepristone, on the Consequences of Withdrawal From Long Term Alcohol Consumption

ALCOHOLISM, Issue 12 2008
Catherine Jacquot
Background:, Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. Materials and Methods:, The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. Results:, Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety-related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. Conclusions:, The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits. [source]

Response to IL-1-Receptor Antagonist in a Child with Familial Cold Autoinflammatory Syndrome

PEDIATRIC DERMATOLOGY, Issue 1 2007
Susan M. O'Connell M.R.C.P.I.
They appear to represent a continuum of one disease characterized by IL-1-mediated inflammation. Until recently, these conditions have been difficult to treat; however, with the advent of IL-1-receptor antagonist therapy, many reports of successful treatment of patients with these autoinflammatory diseases have emerged in the past 2 years. We describe an 8-year-old girl, diagnosed with Familial cold auto-inflammatory syndrome, confirmed by presence of a novel CIAS1 mutation, who was refractory to symptomatic treatment. As frequent attacks of urticaria and associated arthralgia had a debilitating effect on the child's lifestyle, a trial of IL-1-receptor antagonist (anakinra) was instituted. Dramatic sustained clinical improvement was evident within days and serum amyloid and C-reactive protein levels normalized within a month. Although several authors have reported successful use of this agent in children with chronic infantile neurologic, cutaneous, articular syndrome, we believe ours is the first report of successful treatment with anakinra in a young child with familial cold auto-inflammatory syndrome. [source]

Prasugrel , ein neuer ADP-Rezeptor-Antagonist.

PHARMAZIE IN UNSERER ZEIT (PHARMUZ), Issue 4 2009
Prodrug -Aktivierung als entscheidender Unterschied
Mit der Zulassung des P2Y12 -Antagonisten Prasugrel (Efinet®) steht zum ersten Mal eine Alternative zum "Goldstandard" Clopidogrel für die duale Plättchenhemmung bei ACS zur Verfügung. Er fügt sich gut in das Bild der zeitlichen Entwicklung der Therapie des ACS ein. Im Laufe der letzten 20 Jahre ist sie sukzessive wirksamer geworden, allerdings um den Preis höherer Blutungsraten (Abb. 9). Es bleibt abzuwarten, ob sich der unter kontrollierten Studienbedingungen gefundene Netto- Benefit auch im klinischen Alltag bestätigen wird. Wie üblich erlaubt erst die Post-Marketing-Surveillance eine abschließende Beurteilung der Sicherheit. Weitere Studien werden zeigen, welche Patienten von Prasugrel profitieren und wie es optimal anzuwenden ist. Im Juni 2008 startete die TRIOLOGY ACS-Studie (NCT00699998) mit mehr als 10.000 Patienten zum Vergleich von Prasugrel mit Clopidogrel bei Patienten mit UA/NSTEMI, bei denen eine medikamentöse Behandlung angezeigt ist. Hierbei wird die Therapie mit Prasugrel mit einer AD von nur 30 mg begonnen, die ED beträgt je nach Alter und Gewicht 5 oder 10 mg. Das Beispiel der Clopidogrel-Resistenz veranschaulicht, dass es prinzipiell von Vorteil ist, wenn es nicht nur eine Therapieoption für die Plättchenhemmung beim ACS gibt. Denn damit besteht die Möglichkeit, die für den einzelnen Patienten jeweils am besten geeignete Strategie auszuwählen. Neben Prasugrel befinden sich weitere Plättchenhemmstoffe in der Entwicklung. Bereits in Phase-III-Studien werden derzeit drei Kandidaten geprüft: Ticagrelor, ein oraler, im Gegensatz zu den Thienopyridinen direkt und reversibel wirkender P2Y12 -Antagonist, Cangrelor (AR-C69931MX), ebenfalls ein direkter, reversibler P2Y12 -Antagonist, jedoch für die intravenöse, kurzfristige Akuttherapie, sowie SCH 530348, ein oraler Thrombin-Rezeptorantagonist, der selektiv an PAR-1 (Protease-Activated Receptor) bindet. Ein weiterer Aspekt der Forschung ist die Evaluation des Potentials einer individualisierten Therapie, die auf den Ergebnissen von Point-of-Care -Testung der Plättchenfunktion basiert oder sich am Vorliegen genetischer Polymorphismen orientiert. [source]

Promotion of PDT Efficacy by a Bcl-2 Antagonist

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2008
David Kessel
Photodynamic therapy (PDT) directed against the endoplasmic reticulum (ER) is also known to target antiapoptotic Bcl-2 family proteins. This effect is associated with the initiation of both apoptosis, a cell death pathway, and autophagy, an organelle recycling system that can lead to survival or cell death. In this study, we examined the ability of the Bcl-2 antagonist HA14-1 to promote the photodynamic efficacy of PDT directed at the ER. At concentrations that independently caused only a small loss of viability, HA14-1 markedly enhanced the proapoptotic and phototoxic effects of ER photodamage. These results provide additional evidence that the antiapoptotic properties of Bcl-2 constitute an important determinant of photokilling, and demonstrate that synergistic effects can result when PDT is coupled with pharmacologic suppression of Bcl-2 function. [source]

Effect of Suppression of FSH with a GnRH Antagonist (Acyline) Before and During Follicle Deviation in the Mare

REPRODUCTION IN DOMESTIC ANIMALS, Issue 3 2009
CM Checura
Contents A GnRH antagonist (Acyline) was used to study the role of FSH in early development of a follicular wave in 61 mares. In Experiment 1, a single dose of 3 mg per mare, compared with 0 and 1 mg, suppressed both the FSH and follicle responses to exogenous GnRH. In Experiment 2, high concentrations of FSH were induced by two successive ablations of all follicles , 6 mm on days 10 and 13 (day 0 = ovulation). A single treatment with Acyline resulted in significantly greater suppression of plasma concentrations of FSH than a single treatment with charcoal-extracted follicular fluid (source of inhibin) or oestradiol. Suppression of FSH was not significantly different between the group treated with Acyline alone and a group treated with a combination of Acyline, inhibin and oestradiol. In Experiment 3, all follicles were ablated on day 10 to induce an FSH surge and a new follicular wave. Acyline treatment on day 10 resulted in an immediate decrease in FSH, without a significant effect on day of emergence of a new wave or growth of follicles from 7 to 11 mm on days 11,13. Treatment on day 15, a day before expected follicle deviation and after the peak of the wave-stimulating FSH surge, resulted in an immediate decrease in FSH and cessation of follicle growth. Results indicated that growth of follicles for about 2 days after wave emergence was independent of FSH. In contrast, during the decline in the wave-stimulating FSH surge and before follicle deviation, growth of follicles was dependent on FSH. [source]

ORIGINAL ARTICLE: Leukocyte Activation and Circulating Leukocyte-Derived Microparticles in Preeclampsia

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2009
Christianne A.R. Lok
Problem, Preeclampsia shows characteristics of an inflammatory disease including leukocyte activation. Analyses of leukocyte-derived microparticles (MP) and mRNA expression of inflammation-related genes in leukocytes may establish which subgroups of leukocytes contribute to the development of preeclampsia. Method of Study, Blood samples were obtained from preeclamptic patients, normotensive pregnant and non-pregnant controls. sL-selectin and elastase were measured by ELISA. mRNA was isolated from leukocytes and gene expression was determined by multiplex ligation-dependent probe amplification (MLPA). MP were characterized by flow cytometry. Results, Altered concentrations of sL-selectin and elastase confirmed leukocyte activation in preeclampsia. These leukocytes showed up-regulation of Nuclear Factor of Kappa light chain gene enhancer in B Cells inhibitor (NF,B-1A) and cyclin-dependent kinase inhibitor (CDKN)-1A compared with normotensive pregnant women. interleukin-1 Receptor Antagonist (IL-1RA) and tumor necrosis factor (TNF)-R1 were increased compared with those in non-pregnant controls. Monocyte-derived MP were elevated in preeclamptic patients compared with pregnant women. The numbers of cytotoxic T-cell-derived and granulocyte-derived MP were elevated compared with those of non-pregnant women. Conclusion, Leukocytes are activated in preeclampsia. A pro-inflammatory gene expression profile is not prominent, although differences in mRNA expression can be detected. Increased levels of particular subsets of leukocyte-derived MP reflect activation of their parental cells in preeclampsia. [source]

Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice

ARTHRITIS & RHEUMATISM, Issue 9 2003
Hitoshi Hasegawa
Objective To examine whether chemokine antagonists inhibit the initiation and progression of lupus nephritis in MRL/lpr mice. Methods NH2 -terminal,truncated monocyte chemoattractant protein 1 (MCP-1)/CCL2 or thymus and activation,regulated chemokine (TARC)/CCL17 analogs were inserted into the pCXN2 expression vector and transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, established from an MRL/gld mouse. Results MCP-1 antagonist, or TARC antagonist,transfected MRL/N-1 cells were injected subcutaneously into MRL/lpr mice ages 7 weeks (before the onset of lupus nephritis) and 12 weeks (at the early stage of the disease). After 8 weeks, mice bearing the MCP-1 antagonist showed markedly diminished infiltration of macrophages and T cells, glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis compared with control mice. This seemed to be due to decreased production of interferon-, and interleukin-2 in the kidney. In contrast, there was no significant difference in renal damage between mice bearing TARC antagonist and control mice. Conclusion We established a new system using MRL/N-1 cells that allows long-term observation of the effects of chemokine antagonists on lupus nephritis in MRL/lpr mice. We also showed that the MCP-1 antagonist ameliorated the initiation and progression of lupus nephritis and of renal vasculitis, which might provide a new approach to the treatment of the disease. [source]

Pharmacological Profile and Therapeutic Potential of BM-573, a Combined Thromboxane Receptor Antagonist and Synthase Inhibitor

CARDIOVASCULAR THERAPEUTICS, Issue 1 2005
Alexandre Ghuysen
ABSTRACT BM-573 (N-terbutyl-N,-[2-(4,-methylphenylamino)-5-nitro-benzenesulfonyl]urea), a torsemide derivative, is a novel non-carboxylic dual TXA2 synthase inhibitor and receptor antagonist. The pharmacological profile of the drug is characterized by a higher affinity for the thromboxane receptor than that of SQ-29548, one of the most powerful antagonists described to date, by a complete prevention of human platelet aggregation induced by arachidonic acid at a lower dose than either torsemide or sulotroban, and by a significantly prolonged closure time measured by the platelet function analyser (PFA-100®). Moreover, at the concentrations of 1 and 10 ,M, BM-573 completely prevented production of TXB2 by human platelets activated by 0.6 mM of arachidonic acid. BM-573 prevents rat fundus contraction induced by U-46619 but not by prostacyclin or other prostaglandins. Despite possessing a chemical structure very similar to that of a diuretic torsemide, BM-573 has no diuretic activity. BM-573 does not prolong bleeding time and, unlike some of the other sulfonylureas, has no effect on blood glucose levels. In vivo, BM-573 appears to have antiplatelet and antithrombotic activities since it reduced thrombus weight and prolonged the time to abdominal aorta occlusion induced by ferric chloride. BM-573 also relaxed rat aorta and guinea pig trachea precontracted with U-46619. In pigs, BM-573 completely antagonized pulmonary hypertensive effects of U-46619 and reduced the early phase of pulmonary hypertension in models of endotoxic shock and pulmonary embolism. Finally, BM-573 protected pigs from myocardial infarction induced by coronary thrombosis. These results suggest that BM-573 should be viewed as a promising therapeutic agent in the treatment of pulmonary hypertension and syndromes associated with platelet activation. [source]

The Preclinical Pharmacology of BIBN4096BS, a CGRP Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 1 2005
Debbie L. Hay
ABSTRACT CGRP is an important neuropeptide found throughout the cardiovascular system. However, until recently it has been difficult to define its pharmacology or physiological role because of the lack of suitable antagonists. BIBN4096BS is a high-affinity, non-peptide antagonist that shows much greater selectivity for human CGRP1 receptors compared to any other drug. Its pharmacology has been defined with studies on transfected cells or cell lines endogenously expressing receptors of known composition. These have allowed confirmation that in many human blood vessels, CGRP is working via CGRP1 receptors. However, it also interacts with other CGRP-activated receptors, of unknown composition. In vivo, clinical studies have shown that BIBN4096BS is likely to be useful in the treatment of migraine. It has also been used to define the role of CGRP in phenomena such as plasma extravasation and cardioprotection following ischemia. [source]

Clinical and Experimental Aspects of Olmesartan Medoxomil, a New Angiotensin II Receptor Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 4 2004
Kazunori Yoshida
ABSTRACT Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de-esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P-450 and has a dual route of elimination, by kidneys and liver. In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10,80 mg dose-dependently reduced diastolic blood pressure (DBP). Troughto-peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once-daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24-h DBP and SBP were similar to those of cuff DBP measurement. In mild-to-moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24-h blood pressure. In lowering DBP olmesartan medoxomil, at 10,20 mg/day, was as effective as atenolol at 50,100 mg/day. In mild-to-moderate hypertensive patients, olmesartan medoxomil, at 5,20 mg once daily, was more effective than captopril at 12.5,50 mg twice daily. At 20,40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5,10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases. [source]

An Overview of SR121463, a Selective Non-Peptide Vasopressin V2 Receptor Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 3 2001
C. Serradeil-Le Gal
ABSTRACT SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V2 receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2 receptors and exhibits a remarkably selective V2 receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2 receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2 receptor mutant. In vitro, SR1 21463 rescued misfolded V2 AVP receptor mutants by increasing cell surface expression and restoring V2 function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2 (or V2 -like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2 receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2 receptors. Pure V2 receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2 receptors (e.g., glaucoma). [source]

UR-3216: A Manageable Oral GPIIb/IIIa Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 1 2001
Kosuke Baba
ABSTRACT UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is <1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases. [source]

A Small-Molecule Antagonist of the Hedgehog Signaling Pathway

CHEMBIOCHEM, Issue 16 2007
Jongkook Lee Dr.
Shadow the Hedgehog. JK184 (illustrated in the scheme) was identified as an antagonist of Hedgehog signaling through a cell-based screen of chemical libraries. Results from biochemical and cellular experiments suggest that JK184 functions by inhibiting class IV alcohol dehydrogenase. This molecule should serve as a useful tool for studying Hedgehog signaling. [source]

The Use of Three-Dimensional Shape and Electrostatic Similarity Searching in the Identification of a Melanin-Concentrating Hormone Receptor 1 Antagonist

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2006
Steven W. Muchmore
To aid in the identification of novel melanin-concentrating hormone receptor 1 (MCHr1) antagonists, a unique virtual library of readily synthesized molecules was designed and assembled based on 323 monomer compounds containing reactive moieties in combination with 30 core molecules having diamine functionality. The resulting library of 3 129 870 molecules was searched using three-dimensional shape similarity measures that were complimented with a novel electrostatic distribution similarity-matching algorithm. One of the top scoring hits in this library was synthesized and characterized for MCHr1 antagonism, where it exhibited at least a threefold improvement in binding affinity and cellular potency relative to the parent MCHr1 ligand. This work demonstrates that the use of shape and electrostatic similarity matching in combination with a well-designed virtual library can be used to augment standard medicinal chemistry techniques. [source]

ChemInform Abstract: Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine as Novel NMDA Receptor Antagonist.

CHEMINFORM, Issue 27 2010
Syed Masood Husain
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]

ChemInform Abstract: Synthesis and Characterization of a Peripherally Restricted CB1 Cannabinoid Antagonist, URB447, that Reduces Feeding and Body-Weight Gain in Mice.

CHEMINFORM, Issue 26 2009
Jesse LoVerme
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]

ChemInform Abstract: The Discovery of GSK221149A: A Potent and Selective Oxytocin Antagonist.

CHEMINFORM, Issue 26 2008
John Liddle
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]

Efficient Enantioselective Formal Synthesis of Ro 67-8867, a NMDA 2B Receptor Antagonist.

CHEMINFORM, Issue 42 2005
Ingrid Dechamps
No abstract is available for this article. [source]

2-Substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b] [1,5]oxazocin-5-one as a Structurally New NK1 Antagonist.

CHEMINFORM, Issue 28 2005
Shigeki Seto
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Efficient Synthesis of CCR5 Antagonist, 2,3-Dihydro-1-benzothiepine Derivatives by Improved Intramolecular Claisen Type Reaction Using Dialkylcarbonate.

CHEMINFORM, Issue 15 2005
Tomomi Ikemoto
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

A General Approach to (5S,6R)-6-Alkyl-5-benzyloxy-2-piperidinones: Application to the Asymmetric Syntheses of Neurokinin Substance P Receptor Antagonist (-)-L-733,061 and (-)-Deoxocassine.

CHEMINFORM, Issue 1 2005
Liang-Xian Liu
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Synthesis, ,-Adrenoceptor Pharmacology and Toxicology of S-(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2- (3,4-dimethoxyphenyl)ethylamino)propane Hydrochloride, a Short Acting ,1 -Specific Antagonist.

CHEMINFORM, Issue 23 2003
Graham P. Jackman
No abstract is available for this article. [source]

Use of an Isopropyl Ester Moiety as a Sulfonic Acid Protecting Group in a Greatly Improved Synthesis of an Arylsulfonic Acid-Based Follicle Stimulating Hormone Antagonist.

CHEMINFORM, Issue 51 2002
Jay Wrobel
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

ChemInform Abstract: Syntheses and Bioactivities of Novel Carbamates Combining Platelet Activating Factor (PAF) Receptor Antagonist with Thromboxane Synthase Inhibitor (TxSI).

CHEMINFORM, Issue 37 2002
Masakazu Fujita
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]