Abstract：
:Nerve growth factor (NGF) is known to regulate the development and survival of select populations of neurons via its binding/activation of the TrkA and p75(NTR) receptors. However, in some physiological circumstances NGF dysregulation can result in debilitating pathologies, including diabetic neuropathies, interstitial cystitis and fibromyalgia. Thus, the identification of small molecules which inhibit NGF signalling have significant therapeutic potential. PD 90780, Ro 08-2750, and ALE 0540 are small molecules that have been reported to bind and inhibit NGF activity. Importantly, the docking site of these compounds is hypothesised to occur at the loop I/IV cleft of NGF-a region which is required for efficient and selective binding of this neurotrophin to its receptor(s). Molecular modelling predicts a number of previously reported NGF antagonists (PD 90780, ALE 0540, and Ro 08-2750) share conserved molecular features, and these drug-like small molecules have the ability to bind and modify the molecular topology of NGF. In order to understand the putative mechanism of binding, we synthesised a pyrazoloquinazolinecarboxilate analogue series and tested each compound in an NGF-dependent PC12 cell differentiation assay. In vitro data confirms that the pyrazoloquinazolinecarboxilate analogues functionally inhibit NGF's effects on PC12 cell differentiation. The results of this study provide evidence to refine the docking mode of pyrazoloquinazolinecarboxilate based compounds for the purposes of inhibiting NGF in vitro. In addition, we identified series analogue PQC 083 (IC50=7.0 µM; CI=5.4-10.1 µM) which displays markedly higher potency than previously described NGF antagonists.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Eibl JK,Strasser BC,Ross GMdoi
10.1016/j.ejphar.2013.03.029subject
Has Abstractpub_date
2013-05-15 00:00:00pages
30-7issue
1-3eissn
0014-2999issn
1879-0712pii
S0014-2999(13)00219-7journal_volume
708pub_type
杂志文章abstract：:Several structural analogs of mazindol were tested as inhibitors of the uptake of [3H] dopamine in rat neostriatum, of [3H] norepinephrine in rat occipital cortex and of [3H] serotonin in whole rat brain. A rather wide range of potencies was observed but a number of the drugs were even more potent than mazindol as upt...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(81)90030-3
更新日期：1981-05-08 00:00:00
abstract：:The aim of the present study was to find out the mechanism by which the inflammatory mediator, bradykinin, induces an increase of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) in enteric neurons. For this purpose, ganglia in the isolated submucosa from rat colon were loaded with the Ca(2+)-sensitive dye, fura-2, an...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2012.02.001
更新日期：2012-04-15 00:00:00
abstract：:This review focuses on alpha(1)-adrenoceptor phosphorylation and function. Most of what is currently known is based on studies on the hamster alpha(1B)-adrenoceptor. It is known that agonist stimulation leads to homologous desensitization of these receptors and current evidence indicates that such decrease in receptor...
journal_title：European journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1016/s0014-2999(99)00896-1
更新日期：2000-02-11 00:00:00
abstract：:Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2020.173760
更新日期：2021-02-05 00:00:00
abstract：:A decrease of 30% was observed in the density of peripheral-type benzodiazepine binding sites in platelets of nine schizophrenics maintained on chronic neuroleptic treatment as compared to platelets of six untreated schizophrenics and 15 healthy volunteers. The equilibrium dissociation constant for binding by [3H]PK 1...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(86)90500-5
更新日期：1986-02-18 00:00:00
abstract：:The effects of (S)-nafenodone, a new antidepressant, were studied on contraction and 45Ca2+ fluxes in rat vascular smooth muscle. In isolated rat aorta (S)-nafenodone, 10(-7) - 10(-4) M, inhibited the contractions induced by 80 mM KCl (IC50 = 1.4 +/- 0.4 x 10(-5) M) and 10(-5) M noradrenaline (IC50 = 1.2 +/- 0.2 x 10(...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(93)90734-y
更新日期：1993-02-23 00:00:00
abstract：:The precursor to 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan, (5-HTP, 5-50 mg.kg-1) administered subcutaneously (s.c.) to conscious, fed mice caused a dose dependent increase in faecal pellet and fluid output. To avoid provoking watery diarrhoea, all experiments were performed using 5-HTP at 10 mg.kg-1. This dose ...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(96)00296-8
更新日期：1996-07-18 00:00:00
abstract：:[D-Met2,Pro5]enkephalinamide (DMPEA) strongly activated cardioinhibitory vagal efferents and elicited bradycardia when perfused through the cerebroventricular system of anaesthetized dogs. These effects were concentration-dependent but plateaued at an intraventricular concentration of 200 micrograms/ml. At this maxima...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(85)90216-x
更新日期：1985-04-02 00:00:00
abstract：:Anorexia and muscle wasting are frequently observed in cancer patients and influence their clinical outcome. The better understanding of the mechanisms underlying behavioral changes and altered metabolism yielded to the development of specialized nutritional support, which enhances utilization of provided calories and...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2011.06.060
更新日期：2011-09-01 00:00:00
abstract：:Mice, subjected footshock, showed a significant increase of pain threshold and motor suppression immediately after the footshock and both effects were partially antagonized by pretreatment with naloxone at high doses. The magnitude of footshock-induced analgesia, but not motor suppression, was significantly less in mo...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(83)90287-x
更新日期：1983-09-02 00:00:00
abstract：:In the present study 12 of 13 untreated pigs died of ventricular fibrillation during three 10 min episodes of left anterior descending coronary artery occlusion interrupted by 20 min of reperfusion. The selective beta-adrenoceptor antagonist bevantolol in a dose of 1.5 mg X kg-1, but not 0.5 mg X kg-1, offered nearly ...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(85)90645-4
更新日期：1985-05-20 00:00:00
abstract：:The aim of the present study was to determine the effect of a calcium channel blocker on renal function, urinary endothelin excretion and endothelin receptor number in rats. Administration of cyclosporine resulted in a significant impairment of renal function when measured by either [14C]inulin or 24 h creatinine clea...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(91)90132-a
更新日期：1991-02-26 00:00:00
abstract：:The binding characteristics of [3H]gabapentin, the radiolabelled analogue of the novel anticonvulsant gabapentin (1-(aminomethyl)cyclohexaneacetic acid) were studied using purified synaptic plasma membranes prepared from rat cerebral cortex. In 10 mM HEPES buffer [3H]gabapentin bound to a single population of sites wi...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0922-4106(93)90155-3
更新日期：1993-02-15 00:00:00
abstract：:The molecular mechanism underlying the activity of the novel antiepileptic drug retigabine is not yet fully understood. The aim of this study was to investigate whether retigabine interacts directly with the GABA(A) receptor complex (gamma-aminobutyric acid). Receptor-binding assays were conducted using rat brain memb...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(03)01426-2
更新日期：2003-03-19 00:00:00
abstract：:The metabotropic glutamate receptor subtype 5 (mGlu5) and glutamatergic neurotransmission are associated with the pathophysiology of disorders such as anxiety, depression or chronic pain. Human and rat mGlu5 receptors have been cloned and characterized previously. We now describe the cloning of the mouse mGlu5b recept...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2007.10.004
更新日期：2008-01-28 00:00:00
abstract：:Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two ne...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2008.10.048
更新日期：2008-12-28 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(97)81936-x
更新日期：1997-11-05 00:00:00
abstract：:Tacrine and physostigmine were tested for direct nicotinic actions on Xenopus oocytes microinjected with Torpedo electroplaque membranes. In this preparation, responses to acetylcholine arise 6-8 h after microinjection, due to the incorporation of nicotinic receptors into the plasma membrane by a process not involving...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(98)00793-6
更新日期：1998-12-18 00:00:00
abstract：:Elevated fatty acid levels play a pathogenic role in the development of insulin resistance, associated with type 2 diabetes. Interventions with ability to ameliorate fatty acid-induced insulin resistance might be useful for the management of diabetes. Here, we explored the effect of the diastereomeric mixture of calop...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2014.10.049
更新日期：2015-01-05 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(02)02149-0
更新日期：2002-09-20 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(92)90011-r
更新日期：1992-09-10 00:00:00
abstract：:The effects of the delta2-opioid receptor agonist, deltorphin II, on extracellular levels of dopamine in the rat nucleus accumbens were investigated in awake animals by in vivo brain microdialysis. In agreement with previous studies, perfusion of deltorphin II (50.0 nmol) into the nucleus accumbens significantly incre...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2004.03.028
更新日期：2004-04-26 00:00:00
abstract：:Type 2 diabetes mellitus (T2DM) is known to be associated with increased risk of cognitive impairment including Alzheimer disease. Recent studies have suggested an interaction between angiotensin II and N-methyl-d-aspartic acid (NMDA) glutamate receptors. We previously reported that stimulation of the angiotensin II t...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2013.12.015
更新日期：2014-02-05 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(96)00178-1
更新日期：1996-06-13 00:00:00
abstract：:Recent reports show that the nuclear factor-κB (NF-κB) can control numerous genes encoding inflammatory and nociceptive mediators and play an important role in the development of central pain sensitization. The aim of the present study is to assess the role of NF-κB signal pathway and its downstream pro-inflammatory c...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2012.02.017
更新日期：2012-05-05 00:00:00
abstract：:Three peptide components of atrial natriuretic factor (ANF) caused relaxation of carbachol-contracted guinea-pig isolated tracheal smooth muscle. These were the 1-28, 5-28 and 5-27 peptide sequences (ANF(1-28), ANF-(5-28) and ANF-(5-27)). The peptides were 10-30 times more potent in epithelium-denuded than in epitheli...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(92)90328-2
更新日期：1992-03-03 00:00:00
abstract：:The failure of alpha 1-adrenoceptor antagonists, prazosin and indoramin, to cause a reflex tachycardia was investigated in the anaesthetised cat. Recordings were made of preganglionic sympathetic nerve activity from the third or fourth white ramus communicans, femoral arterial conductance, heart rate and blood pressur...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(84)90054-2
更新日期：1984-11-27 00:00:00
abstract：:Effects of PGI2 upon pulmonary vascular resistance and systemic arterial pressure of near term fetuses were evaluated in anesthetized, exteriorized, unventilated fetal lambs by means of an open-chest, pump-perfused lung preparation. These effects were compared to those of PGE1 and PGE2 in the same animals. Intrapulmon...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(79)90405-9
更新日期：1979-02-15 00:00:00
abstract：:Population spikes associated with the paired pulse ratio protocol were used to measure the presynaptic inhibition of corticostriatal transmission caused by mu-opioid receptor activation. A 1 microM of [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO), a selective mu-opioid receptor agonist, enhanced paired pulse fa...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(02)02877-7
更新日期：2003-02-21 00:00:00
abstract：:In the present study, we describe the role of inositol trisphosphate in the signalling pathway that leads to the elevation of cytosolic-free Ca2+ in rat neutrophils stimulated with magnolol, a compound isolated from the cortex of Magnolia officinalis. Magnolol increased [Ca2+]i, by stimulating Ca2+ release from intern...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(98)00363-x
更新日期：1998-07-10 00:00:00
