Abstract:
BACKGROUND AND PURPOSE:Selective oestrogen receptor (ER) modulators (SERMs) are of great value in the treatment of breast cancer and osteoporosis. The aim of this study was to characterize pharmacologically a new class of SERMs synthesized based on the core structure of raloxifene. EXPERIMENTAL APPROACH:Competitive receptor binding and luciferase-based reporter methods were used to study the bioactivities of raloxifene analogues, followed by efficacy determination in breast cancer cell proliferation assay. ER antagonist effects were investigated in female rats by measuring uterine and mammary gland growth, using wet weight, BrdU incorporation and terminal end bud (TEB) as indicators. KEY RESULTS:Five analogues, belonging to two different structural series and display higher binding affinities for ERalpha than ERbeta were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ERalpha or ERbeta and oestrogen-response element-driven luciferase. The estimated IC(50) value was 0.52 nM for ERalpha and 2.94 nM for ERbeta, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 microM. Y134 suppressed oestrogen-stimulated proliferation of ER-positive human breast cancer MCF-7 and T47D cells. At an identical dose, administered to ovariectomized rats, Y134 was more effective than raloxifene at arresting oestrogen-induced outgrowth of TEB and mammary gland DNA synthesis, but their inhibitory effects on the uterus were comparable. CONCLUSIONS AND IMPLICATIONS:Y134 is a potent ER antagonist with better mammary gland selectivity than raloxifene and shows potential for development as a new SERM for therapeutic use.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Ning M,Zhou C,Weng J,Zhang S,Chen D,Yang C,Wang H,Ren J,Zhou L,Jin C,Wang MWdoi
10.1038/sj.bjp.0706960subject
Has Abstractpub_date
2007-01-01 00:00:00pages
19-28issue
1eissn
0007-1188issn
1476-5381pii
0706960journal_volume
150pub_type
杂志文章abstract::1. Different 5-hydroxytryptamine (5-HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5-HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction betwee...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14138.x
更新日期:1990-11-01 00:00:00
abstract::1. Conventional microelectrode techniques were used for intracellular recordings of the transmembrane electrical potentials, the effects of berberine were studied on canine cardiac Purkinje and ventricular muscle fibres and on rabbit atrial fibres. 2. Berberine (3-30 microM) increased in a concentration-dependent mann...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb12836.x
更新日期:1993-02-01 00:00:00
abstract::1. The subtypes of endothelin receptors that mediate the effects of endothelin-1 (ET-1) on mean arterial pressure (MAP), heart rate (HR), mean circulatory filling pressure (MCFP), arterial resistance (RA), cardiac output (CO) and venous resistance (RV) were characterized in 9 groups of pentobarbitone-anaesthetized rat...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701474
更新日期:1997-11-01 00:00:00
abstract::Photorelaxation of vascular smooth muscle (VSM) is caused by the release of nitric oxide (NO) from a finite molecular store that can be depleted by irradiating pre-contracted arteries with visible light. The ability of an 'exhausted' vessel to respond to a further period of illumination is lost temporarily but then re...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703499
更新日期:2000-08-01 00:00:00
abstract::We have examined whether modulation of the polyamine biosynthetic pathway, through inhibition by alpha-difluoromethylornithine (DFMO) of the rate limiting enzyme, ornithine decarboxylase (ODC), modulates NO synthesis in J774 macrophages. DFMO potentiated LPS-stimulated nitrite production in both a concentration- and t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702231
更新日期:1998-12-01 00:00:00
abstract::1. We have characterized the 5-hydroxytryptamine (5-HT)-induced calcium signalling in endothelial cells from the human pulmonary artery. Using RT-PCR we show, that of all cloned G-protein coupled 5-HT receptors, these cells express only 5-HT1D beta, 5-HT2B and little 5-HT4 receptor mRNA. 2. In endothelial cells 5-HT i...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb16700.x
更新日期:1996-03-01 00:00:00
abstract::In non-allergic subjects, histamine induced a reduction of minimal nasal cross-sectional area (Amin) and an increase in albumin release into nasal lavage. The effect of histamine on albumin release was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), 1 mumol but not by D-NAME, 1 mumol. L-NAME,...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb16653.x
更新日期:1995-09-01 00:00:00
abstract::A linear correlation between amplitude of miotic response and initial pupil diameter has been demonstrated in rabbits using various concentrations of pilocarpine HC1. The same correlation was found when published results in humans using carbachol were examined and it is likely that the correlation also applies to pilo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb10635.x
更新日期:1970-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Agonists of the M(2) muscarinic acetylcholine receptor (mAChR) increase mRNA for this receptor and mRNA for endothelial and neuronal isoforms of NO synthase (eNOS or nNOS). Here we examine the different signalling pathways involved in such events in rat cardiac atria. EXPERIMENTAL APPROACH:In is...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707180
更新日期:2007-05-01 00:00:00
abstract::1. Experiments were designed to investigate the effects of the inducible nitric oxide synthase (iNOS) stimulator, lipopolysaccharide (LPS), on noradrenaline (NA) responses and on NOS activity and its expression in intact mesenteric resistance arteries (MRAs) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR)...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703552
更新日期:2000-09-01 00:00:00
abstract::The modulation of the gamma-aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage-clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture. Alphaxalone (greater than 30 nM) reversibly and dose-dependently potentiated the amplitude of membrane ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1987.tb11198.x
更新日期:1987-03-01 00:00:00
abstract::1. Juvenile male rats treated with parachlorophenylalanine showed hair loss round the head and neck extending down the chest and abdomen.2. Treated isolated rats did not have this loss of hair, while untreated animals living in the same cage as treated rats lost their hair. The loss therefore seems to be caused by inc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb08518.x
更新日期:1970-02-01 00:00:00
abstract::1. We investigated the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in non-adrenergic non-cholinergic (NANC) contraction in guinea-pig bronchial strips. 2. Forskolin (3 nM to 1 microM) reduced NANC contraction induced by electrical field stimulation (EFS) in a concentration-dependent fashion (-log EC50 wa...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb09027.x
更新日期:1992-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2008.00050.x
更新日期:2009-02-01 00:00:00
abstract::1. Bicyclic compounds with potential thymoleptic properties (Lu-compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs.2. Biochemical and histochemical in vivo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1969.tb08299.x
更新日期:1969-05-01 00:00:00
abstract::The diterpene, forskolin, is shown to produce a concentration-dependent, increase in short circuit current in two epithelial preparations, amphibian skin and rat colon. In the amphibian tissue the increase is sensitive to amiloride and due to an increase in electrogenic transepithelial sodium transport towards the ser...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb09187.x
更新日期:1982-05-01 00:00:00
abstract::Null equations have been derived which, when applied to log10 concentration-tissue state curves for an agonist determined in the presence and absence of a competitive antagonist which also exhibits functional interaction, allow quantitation of the characteristics of the competitive and functional interactant effects. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb08856.x
更新日期:1985-05-01 00:00:00
abstract::1. The effect of several metabotropic ligands and di- or tripeptides were tested on the binding of [3H]-L(+)-2-amino-4-phosphonobutyric acid ([3H]-L-AP4) on rat mGlu4 receptor. For selected compounds, the functional activity was determined on this receptor using the guanosine-5'[gamma-35S]-thiotriphosphate [gamma-35S]...
journal_title:British journal of pharmacology
pub_type: 临床试验,杂志文章
doi:10.1038/sj.bjp.0702885
更新日期:1999-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Prefrontal dopamine release by the combined activation of 5-HT1A and sigma-1 (σ1 ) receptors is enhanced by the GABAA receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes. EXPERIMENTAL APPROACH:Male mice were treated wi...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13692
更新日期:2017-02-01 00:00:00
abstract::1. Human formyl peptide-receptor-like-1 (FPRL-1) is a promiscuous G protein-coupled receptor (GPCR), and belongs to a chemoattractant receptor family protein. This receptor has been reported to interact with various host-derived peptides and lipids involved in inflammatory responses. We described here, a novel role fo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705592
更新日期:2004-01-01 00:00:00
abstract::1. Chronic inhibition of nitric oxide synthase (NOS) provokes a hypertensive state which has been shown to be angiotensin II (Ang-II) dependent. In addition to raising blood pressure, NOS inhibition also causes leukocyte adhesion. The present study was designed to define the role of Ang-II in hypertension and in the l...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703867
更新日期:2001-02-01 00:00:00
abstract::Monoamine oxidase and aldehyde dehydrogenase activity were significantly reduced in the striatum of rats 8 days after lesion of the nigrostriatal nerve pathway caused by 6-hydroxydopamine. Evidence is presented for the existence of an intraneuronal 'dopamine monoamine oxidase' and intraneuronal aldehyde dehydrogenase....
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08238.x
更新日期:1973-05-01 00:00:00
abstract::The effects of the opioid receptor agonist RX783006 and of the opioid receptor partial agonist (+)-meptazinol have been examined on electrically induced twitch responses of the guinea-pig isolated ileum and of the mouse isolated vas deferens. Log10 concentration-tissue state curves were determined for (+)-meptazinol a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1986.tb10246.x
更新日期:1986-07-01 00:00:00
abstract::Association between staphylococcal infection and pathogenesis of upper airways disease has been reported. This study aimed to investigate the mechanisms underlying the rat pulmonary inflammation induced by airway exposure to staphylococcal enterotoxin A (SEA). SEA (0.3-10 ng trachea(-1)) caused dose-dependent neutroph...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706393
更新日期:2005-11-01 00:00:00
abstract::If one drug, B, antagonizes another, A, by producing the opposite physiological effect, the antagonist concentration-effect curves should be affected by the recording system, which limits the range of agonist responses. With pieces of isolated guinea-pig ileum taken from adjacent parts of the same animal, one recorded...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704169
更新日期:2001-08-01 00:00:00
abstract::1 In the guinea-pig vas deferens, grayanotoxin I (G-I), a diterpenic toxin isolated from certain ericaceous plants caused rhythmic contractions which were dose-dependent (5 x 10(-5) M - 10(-3) M); these followed an initial transient contraction.2 The G-I (3 x 10(-4) M)-induced contraction was markedly inhibited or abo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1983.tb08806.x
更新日期:1983-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:An influx drug/proton antiporter of unknown structure has been functionally demonstrated at the blood-brain barrier. This transporter, which handles some psychoactive drugs like diphenhydramine, clonidine, oxycodone, nicotine and cocaine, could represent a new pharmacological target in drug addic...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13258
更新日期:2015-10-01 00:00:00
abstract::(1) The effects on the whole-cell carbachol-induced muscarinic cationic current (mIcat) of antibodies against the alpha-subunits of various G proteins, as well as the effect of a Gbetagamma subunit, were studied in single guinea-pig ileal smooth muscle cells voltage-clamped at -50 mV. Ionized intracellular calcium con...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705289
更新日期:2003-06-01 00:00:00
abstract::Peroxisome proliferator activated receptors (PPAR)s are nuclear transcription factors of the steroid receptor super-family. One member, PPARgamma, a critical transcription factor in adipogenesis, is expressed in ECV304 cells, and when activated participates in the induction of cell death by apoptosis. Here we describe...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703628
更新日期:2000-10-01 00:00:00
abstract::1. This study investigated the importance of renal sympathetic nerves in regulating sodium and water excretion from the kidneys of stroke prone spontaneously hypertensive and 2K1C Goldblatt hypertensive rats anaesthetized with chloralose/urethane (17.5/300 mg initially and supplemented at regular intervals), and prepa...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15621.x
更新日期:1996-08-01 00:00:00