Abstract：
:PPARδ is a ligand-activated receptor that dimerizes with another nuclear receptor of the retinoic acid receptor family. The dimers interact with other co-activator proteins and form active complexes that bind to PPAR response elements and promote transcription of genes involved in lipid metabolism. It appears that various natural fatty acids and their metabolites serve as endogenous activators of PPARδ; however, there is no consensus in the literature on the nature of the prime activators of the receptor. In vitro and cell-based assays of PPARδ activation by fatty acids and their derivatives often produce conflicting results. The search for synthetic and selective PPARδ agonists, which may be pharmacologically useful, is intense. Current rational modelling used to obtain such compounds relies mostly on crystal structures of synthetic PPARδ ligands with the recombinant ligand binding domain (LBD) of the receptor. Here, we introduce an original computational prediction model for ligand binding to PPARδ LBD. The model was built based on EC50 data of 16 ligands with available crystal structures and validated by calculating binding probabilities of 82 different natural and synthetic compounds from the literature. These compounds were independently tested in cell-free and cell-based assays for their capacity to bind or activate PPARδ, leading to prediction accuracy of between 70% and 93% (depending on ligand type). This new computational tool could therefore be used in the search for natural and synthetic agonists of the receptor.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Kahremany S,Livne A,Gruzman A,Senderowitz H,Sasson Sdoi
10.1111/bph.12950subject
Has Abstractpub_date
2015-02-01 00:00:00pages
754-70issue
3eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章,评审abstract：:1. A synthetic oxytocin analogue, [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), has been tested as an antagonist to the actions of oxytocin and vasopressin on the uterus, the mammary gland and blood pressure.2. The analogue inhibited the response of the isolated rat uterus to both...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1970.tb09927.x
更新日期：1970-10-01 00:00:00
abstract：:Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and ...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.13988
更新日期：2018-04-01 00:00:00
abstract：:1. The noradrenaline concentration in the lung was less than 0.5 mug/g in eight animal species.2. In the cat, dog, rabbit and goat, tyramine produced a fall in pulmonary resistance, which was reduced by the administration of either reserpine or cocaine. Although an infusion of noradrenaline increased the content of th...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1970.tb08525.x
更新日期：1970-02-01 00:00:00
abstract：:1. The potassium-sparing diuretic, amiloride, has been shown to inhibit the Na/Ca exchange system in various preparations. The effects of this drug have been investigated on the contractions of guinea-pig aortic strips elicited by reduction of external K, by addition of ouabain and by removal of external Na. 2. Amilor...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb10316.x
更新日期：1988-03-01 00:00:00
abstract：:The opioid receptors are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of opioid receptors have provided a wealth of knowledge on many aspects of opioid receptor p...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.13774
更新日期：2018-07-01 00:00:00
abstract：:1. SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5-HT...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1996.tb15208.x
更新日期：1996-02-01 00:00:00
abstract：:(1) We have investigated the properties of native and haemagglutinin (HA)-tagged neuropeptide Y (NPY) Y(1) receptors after mutation of the palmitoylation site Cys(337) to Ser or Ala. (2) In Chinese hamster ovary cells expressing similar receptor levels, the C337A mutation abolished incorporation of [(3)H]palmitic acid...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705276
更新日期：2003-06-01 00:00:00
abstract：:Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective death of upper and lower motor neurons which ultimately leads to paralysis and ultimately death. Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial mor...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.12476
更新日期：2014-04-01 00:00:00
abstract：:1. Inositol phospholipid hydrolysis was examined in human cerebral cortex slices by a [3H]-inositol prelabelling assay. 2. Enhancement of [3H]-inositol phosphates accumulation was observed in the presence of carbachol, noradrenaline, histamine, 5-hydroxytryptamine (5-HT) and depolarizing concentrations of KCl. 3. Desp...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb12048.x
更新日期：1990-05-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Although botulinum toxin type A (BoNT/A) is approved for chronic migraine treatment, its mechanism of action is still unknown. Dural neurogenic inflammation (DNI) commonly used to investigate migraine pathophysiology can be evoked by trigeminal pain. Here, we investigated the reactivity of crania...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13366
更新日期：2016-01-01 00:00:00
abstract：:1. We have investigated the effects of the selective phosphodiesterase (PDE) type 4 inhibitor, rolipram (0.01-1 microM) on cytosolic Ca2+ fluxes in FMLP-activated human neutrophils, as well as on superoxide production by, and release of elastase from, these cells. 2. Cytosolic Ca2+ fluxes were measured by use of fura-...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701849
更新日期：1998-06-01 00:00:00
abstract：BACKGROUND AND PURPOSE:ARL 67156, 6-N,N-Diethyl-D-beta-gamma-dibromomethylene adenosine triphosphate, originally named FPL 67156, is the only commercially available inhibitor of ecto-ATPases. Since the first report on this molecule, various ectonucleotidases responsible for the hydrolysis of ATP at the cell surface hav...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0707361
更新日期：2007-09-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor agonists display a promising analgesic profile in preclinical studies. However, supraspinal N/OFQ produced hyperalgesia in rodents and such effects have not been addressed in primates. Thus, the aim of this study was to investigate the effects...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13124
更新日期：2015-07-01 00:00:00
abstract：BACKGROUND AND PURPOSE:The sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) plays a role in thermogenesis. The exogenous compound capsaicin increased SERCA-mediated ATP hydrolysis not coupled to Ca²⁺ transport. Here, we have sought to identify endogenous compounds that may function as SERCA uncoupling agents. EXPERIMENTAL A...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2012.01899.x
更新日期：2012-08-01 00:00:00
abstract：:1 In the isolated basilar artery of the rabbit, gamma-aminobutyrate acid (GABA) (ED50 +/- s.e. mean, 2.4 +/- 1.1 x 10(-5) M) produced a relaxation, if the tone had been increased with 5-hydroxytryptamine (5-HT). 2 3-Aminoproprane sulphonic acid (3-APS) produced a similar, but smaller relaxation, while baclofen had no ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1982.tb08770.x
更新日期：1982-01-01 00:00:00
abstract：:1. Taxanes are antineoplastic drugs which have cardiovascular side effects of unknown mechanism. We investigated their influence on blood viscosity and erythrocyte morphology. 2. Whole blood was incubated in vitro with increasing concentrations of Taxol, Taxotere, paclitaxel (0-100 microM) and the vehicles Cremophor-E...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704387
更新日期：2001-11-01 00:00:00
abstract：:1 A study was made of desensitization in chronically denervated and in normally innervated mouse soleus muscles. 2 Very high concentrations of acetylcholine produced small contractions of the innervated muscles; these were reduced in size when the addition was repeated 1 min after wash-out. 3 Desensitization in innerv...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1975.tb07620.x
更新日期：1975-09-01 00:00:00
abstract：:1 Nine antibiotic compounds in common use were studied to determine their ability to affect intestinal motility in vitro, in the guinea-pig ileum and rabbit colon. 2 Ampicillin, doxycycline, mecillinam and metronidazole were without effect over a concentration range which included typical serum levels found when these...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1981.tb10453.x
更新日期：1981-06-01 00:00:00
abstract：:1. Previous studies have shown that the histamine H(1) receptor activates p42/p44 mitogen-activated protein kinases (MAPK) in DDT(1)MF-2 smooth muscle cells via a phosphatidylinositol 3-kinase (PI-3K)-dependent pathway. In this study the effect of histamine H(1) receptor stimulation on protein kinase B (PKB) and p70 S...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704664
更新日期：2002-04-01 00:00:00
abstract：:Prostaglandin E(2) (PGE(2)) increased adenosine 3' : 5'-cyclic monophosphate (cyclic AMP) formation in tracheal epithelial cells and concomitantly decreased the production/secretion of immunoreactive endothelin (irET). Naturally occurring prostanoids and selective and non-selective EP receptor agonists showed the foll...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703886
更新日期：2001-03-01 00:00:00
abstract：:1. A murine macrophage cell line, J774, expressed nitric oxide (NO) synthase activity in response to interferon-gamma (IFN-gamma, 10 u ml-1) plus lipopolysaccharide (LPS, 10 ng ml-1). The enzyme activity was first detectable 6 h after incubation, peaked at 12 h and became undetectable after 48 h. 2. The decline in the...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb12886.x
更新日期：1993-03-01 00:00:00
abstract：:1. The kinetics of glycine-sensitive, N-methyl-D-aspartate (NMDA) receptor desensitization were investigated in cultured neurones with the patch clamp technique. 2. The degree of fast NMDA-receptor desensitization was inversely related to glycine concentration. Thus, increasing concentrations of glycine from 30 nM to ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb13556.x
更新日期：1993-05-01 00:00:00
abstract：:1. Phenylarsine oxide (PAO) is commonly used to inhibit tyrosine phosphatase activity. However, PAO can affect a variety of different processes because of its ability to promote sulfhydryl oxidation. In the present study, we investigated the effects that PAO has on basal and beta-adrenergically stimulated L-type Ca(2+...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705845
更新日期：2004-06-01 00:00:00
abstract：:In ring preparations of the rabbit external jugular vein contracted with the thromboxane-mimetic U-46619, submicromolar concentrations of 5-hydroxytryptamine (5-HT) and chemically related analogues produced relaxations that were dependent on the integrity of the vascular endothelium. The receptor mediating endothelium...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1987.tb10287.x
更新日期：1987-06-01 00:00:00
abstract：:1. Fluoxetine (Prozac) is widely used as an antidepressant drug and is assumed to be a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI). Claims that its beneficial psychotropic effects extend beyond those in treatment of depression have drawn clinical and popular attention to this compound, raising the q...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701545
更新日期：1997-12-01 00:00:00
abstract：BACKGROUND AND PURPOSE:The dietary trace amines tyramine and beta-phenylethylamine (beta-PEA) can increase blood pressure. However, the mechanisms involved in the vascular effect of trace amines have not been fully established. The purpose of this study was to evaluate whether trace amine-dependent vasoconstriction was...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/bjp.2008.286
更新日期：2008-10-01 00:00:00
abstract：BACKGROUND AND PURPOSE:This study represents a novel characterisation of KCNQ-encoded potassium channels in the vasculature using a variety of pharmacological and molecular tools to determine their role in contractility. EXPERIMENTAL APPROACH:Reverse transcriptase polymerase chain reaction (RT-PCR) experiments were un...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0707284
更新日期：2007-07-01 00:00:00
abstract：:Initiation of 60 min ischaemia to rat isolated hearts produced a depression in developed tension and heart rate. Subsequent reperfusion caused a greatly exacerbated creatine phosphokinase (CPK) efflux and limited functional recovery. Sulphinpyrazone (100 ng ml-1 and 1 microgram ml-1) significantly reduced CPK release,...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1984.tb10138.x
更新日期：1984-09-01 00:00:00
abstract：:1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb14775.x
更新日期：1994-02-01 00:00:00
abstract：:1. We investigated the role of two conserved basic residues in the second transmembrane helix arginine 172 (R172) and lysine 179 (K179) of the VPAC(2) receptor. 2. Vasoactive intestinal polypeptide (VIP) activated VPAC(2) receptors with an EC(50) value of 7 nM, as compared to 150, 190 and 4000 nM at R172L, R172Q and K...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704195
更新日期：2001-08-01 00:00:00
