Abstract:
:Growing evidence recommends incorporating the concept of drug-target residence times within drug development and screening programs. For many targets, systematic research for binding kinetics is emerging and reported, as in case of the histamine H3 receptor. Alternatively, fluorescent methods based on Foerster resonance energy transfer have been reported recently but application of fluorescence polarization to kinetics of unlabeled ligands is not known to us. Thus, we established a radiolabel-free, real-time resolving method that is compatible to high-throughput-screening programs with the objective to explore the underlying binding kinetics. This method takes benefit of bodilisant as H3 receptor ligand. Thereby, we detected short residence times around 5 min for the H3 receptor ligands ciproxifan, clobenpropit, thioperamide as well as pitolisant. Monitoring association rates, remarkably slower association rate constants were examined for ciproxifan and thioperamide when compared to those of pitolisant or clobenpropit. The affinities for the ligands derived by the kinetic approach differ from affinity estimates in literature using radiolabeled agonists in displacement assays. Further investigation raised exceptional pharmacological properties, consistent with occurrence of secondary binding sites at the H3 receptor. Validation of resulting affinity constants was successfully performed by displacement assays based on fluorescence polarization with bodilisant.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Reiner D,Stark Hdoi
10.1016/j.ejphar.2019.01.041subject
Has Abstractpub_date
2019-04-05 00:00:00pages
112-120eissn
0014-2999issn
1879-0712pii
S0014-2999(19)30068-8journal_volume
848pub_type
杂志文章abstract::D,L-Propranolol given in single doses by gavage or s.c. injection to awake rats, always slowed the heart without affecting blood pressure. Doses of 0.2 mg/100 g injected twice daily lowered systolic pressure after 3 days in DOCA hypertensive but not in normotensive or spontaneously hypertensive rats. When chronic trea...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(77)90038-3
更新日期:1977-06-15 00:00:00
abstract::Inhibition of inducible nitric oxide (NO) synthase during endotoxaemia may be of therapeutic value. We have previously shown that pretreatment of mice with adenosine receptor agonists 1 h before lipopolysaccharide administration results in a dose-dependent reduction of plasma nitrite and nitrate (NOx-) levels. This re...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(96)00677-2
更新日期:1996-12-05 00:00:00
abstract::Pentoxifylline (PTX), a non-specific inhibitor of cAMP phosphodiesterases, is commonly used for treatment of peripheral vascular disorders although its direct action on endothelial cells is not well described. The aim of this study was to determine the influence of PTX on tubule formation and mRNA expression for angio...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2018.03.015
更新日期:2018-05-15 00:00:00
abstract::Atherosclerosis is a leading cause of death worldwide. It is a complex chronic inflammatory disease involving interactions between vascular, circulating and immune cells. B cells play an important role in chronic inflammation producing antibodies and regulating T and natural killer (NKT) cell activation. The role of B...
journal_title:European journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.ejphar.2017.09.002
更新日期:2017-12-05 00:00:00
abstract::Inhibition of glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), also termed N-acetylated alpha-linked acidic dipeptidase (NAALADase), has been shown to protect against ischemic injury presumably via decreasing glutamate and increasing N-acetyl-aspartyl-glutamate (NAAG). NAAG is a potent and selective mGlu3 receptor ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(01)01239-0
更新日期:2001-10-26 00:00:00
abstract::P815, a murine mastocytoma cell line, possesses beta-adrenergic binding sites as assessed by using [3H]dihydroalprenolol (antagonist) and [3H]hydroxybenzylisoproterenol (agonist). The number of binding sites per cell was 29 000 for the agonist and 75 000 for the antagonist, as determined by direct binding assays and i...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(85)90717-4
更新日期:1985-01-22 00:00:00
abstract::Peripheral nerve injury, which gives rise to persistent chronic pain, has become an area of intense research activity, largely because it represents a disorder with a high unmet medical need. In this study, serum biomarkers of the spinal nerve ligation model were successfully investigated with the metabolomic method. ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2009.03.079
更新日期:2009-08-01 00:00:00
abstract::The effects of 2-methylthio ATP, an ATP analogue that is more specific for the P2Y receptor, were investigated on insulin secretion in the anesthetized dog in vivo. 2-Methylthio ATP was infused directly into the pancreaticoduodenal artery for 15 min. The infusion was performed so as to obtain a pancreaticoduodenal art...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(88)90418-9
更新日期:1988-10-11 00:00:00
abstract::Acute administration of an opiate has been suggested to result in the development of supersensitive dopamine receptors. This hypothesis was tested in mice by determining the effect of a single administration of morphine or levorphanol on dopamine agonist-induced stereotypic behaviors and [3H]spiroperidol binding. Admi...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(85)90324-3
更新日期:1985-12-10 00:00:00
abstract::The cerebrovascular actions of bosentan, a novel endothelin antagonist with effects at endothelin ETA and ETB receptors, have been examined in individual pial arterioles on the cortical surface of chloralose-anaesthetised cats. Subarachnoid perivascular microapplication of bosentan (0.3-300 microM) had minimal effect ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(94)90010-8
更新日期:1994-07-21 00:00:00
abstract::Certain neuropeptides, including vasoactive intestinal peptide, inhibit peptidoleukotriene release from platelet activating factor-stimulated rat lung. We have now shown that vasoactive intestinal peptide will also inhibit peptidoleukotriene release from platelet activating factor-stimulated or ovalbumin-challenged gu...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(89)90610-9
更新日期:1989-03-14 00:00:00
abstract::The efficacy of cetirizine in comparison with meclizine, another piperazine H1 receptor antagonist, in rat pleurisy caused by allergen or autacoid was investigated. Sensitization was achieved by subcutaneous injection of a mixture of ovalbumin and aluminium hydroxide. Fourteen days later, the animals were challenged w...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(92)90811-h
更新日期:1992-11-13 00:00:00
abstract::Pteropodine and isopteropodine are heteroyohimbine-type oxindole alkaloid components of Uncaria tomentosa (Willd.) DC, a Peruvian medicinal plant known as cat's claw. In this study, the effects of these alkaloids on the function of Ca(2+)-activated Cl(-) currents evoked by stimulation of G protein-coupled muscarinic M...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(02)01608-4
更新日期:2002-05-24 00:00:00
abstract::Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPARgamma regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid bi...
journal_title:European journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.ejphar.2005.12.048
更新日期:2006-03-08 00:00:00
abstract::In the Brattleboro rat with diabetes insipidus vasopressin V2 receptor mRNA and the mRNA of various adenylyl cyclase (AC) isoforms are moderately reduced compared with those of normal rats. In the present study renal vasopressin V2 receptor mRNA was modestly higher (by 34%), as was expression of AC 5, 6 and 9 mRNAs (u...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(97)01461-1
更新日期:1998-01-02 00:00:00
abstract::The responses of spinothalamic, spinoreticular, and unidentified spinal neurons to intracardiac administration of phenylbiguanide, a 5-HT3 receptor agonist, were examined in anesthetized cats and monkeys. Eighteen neurons were excited, 5 were inhibited, and 12 were unresponsive to this stimulus. Results suggest that c...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(92)90218-s
更新日期:1992-05-27 00:00:00
abstract::The present study was conducted to evaluate the effect of L-3, 4-dihydroxyphenylalanine (L-DOPA) on the daily rhythms of temperature, heart rate and locomotor activity in rats that received a 7-day continuous infusion. Our results indicate that L-DOPA does not induce a loss of the daily rhythmicity of temperature, hea...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(00)00422-2
更新日期:2000-07-28 00:00:00
abstract::Risperidone (R 64 766, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pyperidinyl]ethyl )-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one) has superior effects in treating negative symptoms of schizophrenia and causes less extrapyramidal side effects than traditional antipsychotics. In this study, we employed ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(99)00160-0
更新日期:1999-04-16 00:00:00
abstract::The Langendorff-perfused rabbit heart preparation has been used to study the interaction of isolated rabbit neutrophils with regionally ischaemic myocardium. Short durations of regional ischaemia (10-60 min) and subsequent reperfusion (30 min) of the hearts with neutrophils resulted in a significant time-dependent acc...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(92)94835-j
更新日期:1992-11-17 00:00:00
abstract::The effects of Bay K 8644 and of nifedipine on histamine-induced mechanical and electrical responses were studied in the longitudinal smooth muscle of the ileum and in the taenia coli isolated from the guinea-pig. Nifedipine (10(-9)-10(-7) M) depressed the tonic and phasic components of histamine contraction. Phasic t...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(87)90758-8
更新日期:1987-03-03 00:00:00
abstract::Circadian rhythms in mammals are generated by master pacemaker cells located within the suprachiasmatic nucleus of the hypothalamus. In hamsters, the suprachiasmatic nucleus contains a small collection of cells immunoreactive for substance P, the endogenous ligand of tachykinin neurokinin 1 (NK1) receptors. In additio...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2005.10.012
更新日期:2005-12-19 00:00:00
abstract::We now describe the preparation and characterization of a novel radioligand, 2-[125I]iodo-5-methoxy-carbonylamino-N-acetyltryptamine (2-[125I]MCA-NAT), with high affinity and pharmacological selectivity for melatonin ML2 receptor sites. 2-[125I]MCA-NAT was prepared by introducing an [125I]iodine molecule on carbon 2 o...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(95)00870-5
更新日期:1996-04-22 00:00:00
abstract::The aims of the present study were to examine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on airway smooth muscle cells (ASMCs) proliferation and to address its potential mechanisms. Platelet derived growth factor (PDGF) activated phosphatidylinositol 3-kinase (PI3K)/protein kinase...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2016.09.003
更新日期:2016-11-15 00:00:00
abstract::The inhibitory actions of the Ca2+ antagonist Cd2+, morphine and noradrenaline (exogenously added + endogenously released) on electrically evoked release of [3H]noradrenaline from superfused rat neocortical slices were strongly reduced when release was enhanced by 4-aminopyridine. In the presence of 4-aminopyridine th...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(83)90084-5
更新日期:1983-03-04 00:00:00
abstract::The present study was designed to investigate the antinociception of spirocyclopiperazinium salt compound LXM-10-M (2,4-dimethyl-9-β-m-hydroxyphenylethyl-3-oxo-6, 9-diazaspiro [5.5] undecane chloride) in thermal and chemical pain models, and further to explore the molecular target and potential signal pathway. We asse...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2015.11.056
更新日期:2016-01-05 00:00:00
abstract::The vasodepressor actions of the cyclic endoperoxides PGG2 and PGH2 were compared with those of their products PGD2 and PGE2 using anaesthetised normotensive and genetically hypertensive rats. Given into the aortic arch of normotensives PGE2 was approximately 6 times more potent than PGH2 and 11 times more potent tha...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(76)90133-3
更新日期:1976-10-01 00:00:00
abstract::The 8-substituted 9-ethyladenine derivatives: 8-bromo-9-ethyladenine (ANR 82), 8-ethoxy- 9-ethyladenine (ANR 94), and 8-furyl-9-ethyladenine (ANR 152) have been characterized in vitro as adenosine receptor antagonists. Adenosine is deeply involved in the control of motor behaviour and substantial evidences indicate th...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2005.01.057
更新日期:2005-04-11 00:00:00
abstract::Synaptic transmission in intact pieces of the Torpedo electric organ treated with vesamicol (2-(4-phenylpiperidino)cyclohexanol, formerly AH5183) was elicited by trains of repetitive electrical stimulation at different frequencies. When the frequency of stimulation was increased from 10 to 50 or 100 Hz, micromolar con...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(91)90375-z
更新日期:1991-03-19 00:00:00
abstract::The characteristics of histamine H1-receptors on astrocytes from the cerebral cortex of newborn rats in primary culture were analyzed with a [3H]mepyramine binding assay, and compared with those in the cerebral cortex. The apparent dissociation constant (KD) of [3H]mepyramine binding, the apparent inhibition constants...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(89)90007-1
更新日期:1989-11-28 00:00:00
abstract::Increasing costs, much time consumption and high risk of failure associated with the process of de novo development of new anticancer drugs have prompted the pharmaceutical industry to seek alternative strategies that may facilitate and accelerate the whole process. In particular, the repurposing strategy, known also ...
journal_title:European journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.ejphar.2019.172784
更新日期:2020-01-05 00:00:00