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Antagonist Properties (antagonist + property)

Distribution by Scientific Domains

Medical Sciences	37%
Life Sciences	37%
Chemistry	25%

Selected Abstracts

CALCIUM ANTAGONIST PROPERTY OF CPU228, A DOFETILIDE DERIVATIVE, CONTRIBUTES TO ITS LOW INCIDENCE OF TORSADES DE POINTES IN RABBITS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2007
Zhi-Jiang Huang
SUMMARY 1Torsades de pointes (TDP) is a severe adverse effect during the clinical use of dofetilide, a selective blocker of the rapid component of the delayed rectifier potassium channel (IKr). The present study was designed to test whether CPU228, a derivative of dofetilide with calcium (Ca2+) antagonist properties, could reduce TDP without reducing the blockade of IKr. 2The incidence of TDP in a rabbit model and the effective refractory period (ERP) were measured and compared for dofetilide and CPU228. Suppression of IKr and the L-type Ca2+ current (ICa,L) and the Ca2+ transients of isolated cardiomyocytes were investigated by whole-cell patch-clamp and Fluo-3 dye spectrophotometry. 3The incidence of TDP was greatly reduced by CPU228 relative to dofetilide, occurring in only one of six rabbits compared with five of six rabbits following dofetilide (P < 0.05). In isolated atria, prolongation of ERP by CPU228 was less than that of dofetilide and no reverse frequency dependence was observed. Negative inotropism by CPU228 was significant against positive inotropism by dofetilide. CPU228 inhibited both IKr and ICa,L currents and the IC50 for ICa,L inhibition was 0.909 µmol/L. At 3 µmol/L, CPU228 significantly suppressed the Ca2+ transients. 4CPU228 is able to block ICa,L, contributing to decreased TDP, while also blocking IKr activity. By combined blockade of IKr and ICa,L, CPU228 shares the property of complex Class III anti-arrhythmic agents. [source]

Perinatal exposure to bisphenol-A changes N -methyl- D -aspartate receptor expression in the hippocampus of male rat offspring

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2010
Xiao-Hong Xu
Abstract Bisphenol-A (BPA) is one of the most common environmental endocrine disrupters with mixed estrogen agonist/antagonist properties. The toxicity of BPA has been extensively evaluated in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. The objective of the present study is to evaluate whether or not perinatal maternal exposure to BPA at 0.05, 0.5, 5, 50, and 200 mg/kg/d affects N -methyl- D -aspartate (NMDA) receptor (NMDAR) subunits NR1, NR2A, 2B, estrogen receptor beta (ER,), and aromatase cytochrome P450 (P450arom) protein expressions of hippocampus in male rat offspring during postnatal development. Western-blotting analyses showed that perinatal exposure to BPA significantly affected the expression of NMDAR subunits. At the lower doses of 0.05 to 50 mg/kg/d, BPA concentration dependently inhibited the expression of NMDAR subunits. However, at the higher dose (200 mg/kg/d), the effects of BPA on these subunits were different, with a stronger inhibition of NR1 expression and a slighter inhibition of NR2A, 2B expression when compared with those at the lower dosage of BPA. In addition, perinatal exposure to BPA inhibited the expression of ER, protein, but increased P450arom protein expression in a concentration-dependent manner, especially during the early postnatal period (the first 1,3 postnatal weeks). No significant influence of BPA on P450arom was observed at postnatal week 8. These data suggest that environmental BPA exposure may affect the development of the brain, enhancing the local biosynthesis of estrogen in the brain, inhibiting ER, and NMDAR expressions. Environ. Toxicol. Chem. 2010;29:176,181. © 2009 SETAC [source]

Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of ,2 -adrenergic and serotonin2C receptors: a comparison with citalopram

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2000
M. J. Millan
Abstract Mirtazapine displayed marked affinity for cloned, human ,2A -adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5,-O-(3-[35S]thio)-triphosphate ([35S]-GTP,S) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2 -AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at ,2A -AR and 5-HT2C receptors. [source]

AL-3138 Antagonizes FP Prostanoid Receptor-mediated Inositol Phosphates Generation: Comparison with Some Purported FP Antagonists

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2000
N. A. SHARIF
The aim of this study was to pharmacologically characterize the antagonist properties of a novel prostaglandin F2, (PGF2,) analogue (11-deoxy-16-fluoro PGF2,; AL-3138) using a variety of second-messenger assays of prostaglandin receptor subtypes. A detailed comparison was made between AL-3138 and some purported FP receptor antagonists such as PGF2, dimethylamine, PGF2, dimethylamide, glibenclamide and phloretin using the FP receptor-mediated phosphoinositide turnover assay in A7r5 rat thoracic aorta smooth muscle cells and mouse Swiss 3T3 fibroblasts. The potency and efficacy of AL-3138 as an FP receptor agonist were: EC50 = 72.2 ± 17.9 nM (Emax = 37%) (n = 3) in A7r5 cells and EC50 = 20.5 ± 2.8 nM (Emax = 33%) (n = 5) in 3T3 cells. Being a partial agonist, the antagonist potency of AL-3138 against fluprostenol in A7r5 cells was determined to be: Ki = 296 ± 17 nM (n = 3) and Kb = 182 ± 44nM (n = 5) (-log Kb = 6.79 ± 0.1). AL-3138 exhibited very minimal or no antagonistic effects at EP2, EP4, DP and TP prostaglandin receptors. Both PGF2, dimethylamide and PGF2, dimethylamine were inactive as FP receptor antagonists, whereas phloretin and glibenclamide were very weak and had -log Kb values of 5.28 ± 0.09 (n = 3) and 3.58 ± 0.32 (n = 3), respectively. However, phloretin antagonized functional responses of EP2 and DP prostanoid receptors, and also the V1 , vasopressin receptor. AL-3138 competed for [3H]PGF2, binding to FP receptors with a relatively high affinity (IC50high = 312 ± 95nM) matching its functional antagonist potency. In conclusion, AL-3138 is a more potent and selective FP receptor antagonist than glibenclamide, phloretin, PGF2, dimethylamide and PGF2, dimethylamine and is therefore a unique and novel pharmacological tool to help characterize FP receptor-mediated functions. [source]

Tetraamine-Derived Bifunctional Chelators for Technetium-99m Labelling: Synthesis, Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP-Receptor-Positive Tumours,

CHEMISTRY - A EUROPEAN JOURNAL, Issue 7 2010
Keelara Abiraj Dr.
Abstract Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, 99mTc continues to be the ideal radioisotope for medical-imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O2 to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11-tetraazaundecane derivatives (01,06) containing different functional groups at the 6-position for the conjugation of biomolecules and subsequent labelling with 99mTc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N3 (04) and O -succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl-functionalised tetraamine-based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin-antagonist peptide and subsequent labelling with 99mTc afforded the radiotracer 99mTc-N4-BB-ANT, with radiolabelling yields of >97,% at a specific activity of 37,GBq,,mol,1. An IC50 value of (3.7±1.3),nM was obtained, which confirmed the high affinity of the conjugate to the gastrin-releasing-peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of 99mTc-N4-BB-ANT showed high and specific uptake in PC3 xenografts and in other GRPr-positive organs. The tumour uptake was (22.5±2.6),% injected activity per gram (%,IA,g,1) at 1,h post injection (p.i.). and increased to (29.9±4.0),%,IA,g,1 at 4,h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of 99mTc-N4-BB-ANT warrant its potential candidature for clinical translation. [source]

,1 - and ,2 -Adrenoreceptor Antagonist Profiles of 1- and 2-[, -(4-Arylpiperazin-1-yl)alkyl]-1,2,3-benzotriazoles

CHEMISTRY & BIODIVERSITY, Issue 10 2005
Alessandro Boido
A series of pharmacologically interesting 1- and 2-[, -(4-arylpiperazin-1-yl)alkyl]-1,2,3-benzotriazoles, compounds 1,27, were synthesized (Scheme) and subjected to various biological studies to identify structure,activity relationships (SAR). The new compounds were found to exhibit good non-selective binding affinity towards the ,1 -adrenoreceptor (Table,1). In several cases, high functional antagonism was observed towards the ,1A -, ,1B -, and ,1D -adrenoreceptor subtypes (Table,2). The selectivity for these three subtypes was comparable with or superior to that displayed by the standard drug prazosin. The most-common selectivity rank order was ,1D>,1B>,1A, followed by ,1B>,1D>,1A. In functional experiments, antagonism towards the ,2 -adrenoreceptor was generally low; however, a few compounds were endowed with significant antagonist properties (pA2 values of up to 7.87). [source]