Abstract：
:In the clinic, low efficacy positive GABAA modulators might be preferred to high efficacy positive modulators insofar as low efficacy modulators might have comparatively less abuse and dependence liability. Drug discrimination was used to examine the behavioral effects of L-838,417 and bretazenil, two low efficacy positive GABAA modulators that act at benzodiazepine sites, alone and in combination with benzodiazepines and a neuroactive steroid (alfaxolone). In rhesus monkeys (n = 5) discriminating midazolam, alfaxolone substituted for midazolam. In four monkeys, L-838,417 and bretazenil did not substitute for, but rather dose-dependently antagonized, midazolam; L-838-417 and bretazenil, as well as flumazenil, enhanced the midazolam-like effects of alfaxolone. L-838,417 and bretazenil substituted for midazolam in a fifth monkey. In a separate group of rhesus monkeys (n = 3) that received 5.6 mg kg(-1) per day of diazepam and that discriminated flumazenil, L-838,417 and bretazenil substituted for flumazenil. These results demonstrate that L-838,417, bretazenil, and flumazenil can have agonist or antagonist actions in the same animal depending upon whether they are studied in combination with a higher efficacy positive GABAA modulator acting at the same (benzodiazepine) or a different (neuroactive steroid) site. Thus, combinations of low efficacy positive modulators acting at different sites on the GABAA receptor complex could yield drug mixtures with significant therapeutic effects and with reduced abuse and dependence liability, as compared to higher efficacy positive modulators such as currently available benzodiazepines.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
McMahon LR,France CPdoi
10.1038/sj.bjp.0706550subject
Has Abstractpub_date
2006-02-01 00:00:00pages
260-8issue
3eissn
0007-1188issn
1476-5381pii
0706550journal_volume
147pub_type
杂志文章abstract：BACKGROUND AND PURPOSE:Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. E...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13271
更新日期：2015-11-01 00:00:00
abstract：:Endothelin-1 (ET-1) is a peptide hormone produced within the myocardium which may modulate myocardial contractility in a paracrine-autocrine fashion. In the majority of species, ET-1 has a direct positive inotropic effect on the myocardium that involves both increased myofilament Ca(2+) sensitivity and increased Ca(2+...
journal_title：British journal of pharmacology
pub_type： 评论,杂志文章
doi：10.1038/sj.bjp.0707438
更新日期：2007-10-01 00:00:00
abstract：:Constitutively active mu-opioid receptors (mu* receptors) are reported to be formed following prolonged agonist treatment of cells or whole animals. mu* receptors signal in the absence of activating ligand and a blockade of mu* activation of G-proteins by naloxone and naltrexone has been suggested to underlie the prof...
journal_title：British journal of pharmacology
pub_type： 评论,杂志文章
doi：10.1111/j.1476-5381.2009.00067.x
更新日期：2009-04-01 00:00:00
abstract：:The stoichiometric relationship between adrenoceptors and saturable binding sites for 1,4-dihydropyridines in calcium channels was investigated in human ventricular myocardium. Membrane particles were prepared from heart specimens of patients undergoing open heart surgery. The patients suffered from hypertrophic obstr...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1987.tb11194.x
更新日期：1987-03-01 00:00:00
abstract：:1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse t...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704395
更新日期：2001-12-01 00:00:00
abstract：:The POZ domain Krüppel-like zinc finger transcription repressor (POK family) contains many important molecules, including RP58, Bcl6 and PLZF. They function as transcription repressors via chromatin remodelling and histone deacetylation and are known to be involved in the development and tumourigenesis of various orga...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.15265
更新日期：2020-09-22 00:00:00
abstract：:Lipocortin (annexin) 1 is a putative mediator of the inflammatory effects of glucocorticoids. By flow cytometric analysis (FACS) we have studied the effect of dexamethasone on the cellular localization of lipocortin 1. U-937 cells were incubated with or without 10 nM phorbol 12-myristate 13-acetate (PMA) to induce cel...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb13075.x
更新日期：1994-06-01 00:00:00
abstract：:Cholesterol and oxysterol sulfates are important regulators of lipid metabolism, inflammation, cell apoptosis, and cell survival. Among the sulfate-based lipids, cholesterol sulfate (CS) is the most studied lipid both quantitatively and functionally. Despite the importance, very few studies have analysed and linked th...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.15227
更新日期：2020-08-06 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 Groups of mice were pretreated with the 5-hydroxytryptamine (5-HT) depletors, fenfluramine or p-chlorophenylalanine (PCPA), followed by pethidine or morphine. 2 Fenfluramine alone produced a short lasting analgesia but PCPA was without any effect. 3 Pethidine and morphine both increased hot plate reaction times meas...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1982.tb09177.x
更新日期：1982-04-01 00:00:00
abstract：:Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPARgamma signalling is now believed to be...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705973
更新日期：2004-12-01 00:00:00
abstract：:1. The effects of a rat brain extract containing clonidine-displacing substance (CDS), a putative endogenous imidazoline receptor ligand, on insulin release from rat and human isolated islets of Langerhans were investigated. 2. CDS was able to potentiate the insulin secretory response of rat islets incubated at 6 mM g...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0700964
更新日期：1997-03-01 00:00:00
abstract：:1. Catecholamine release from cat adrenal glands perfused at a high rate (4 ml min-1) at 37 degrees C with modified Krebs solutions lacking Ca and containing 1.2 mM K (hyperpolarizing solution) or 118 mM K (depolarizing solution) was triggered by 10-s pulses of Ca (0.5 mM) in the presence of 118 mM K. Hyperpolarized g...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1989.tb11874.x
更新日期：1989-03-01 00:00:00
abstract：:1. Unique among the phospholipids, phosphatidylserine depresses brain energy metabolism when injected intravenously into mice in the form of sonicated liposomes. The possibility that this effect results from a metabolic transformation of phosphatidylserine is examined in this paper. 2. A strong enhancement of the phos...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1979.tb08708.x
更新日期：1979-12-01 00:00:00
abstract：:1. TRPM8 (CMR1) is a Ca(2+)-permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to ment...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705652
更新日期：2004-02-01 00:00:00
abstract：:1. Our study was aimed at investigating the duration of the bronchodilator action of the antimuscarinc drug glycopyrrolate compared to tiotropium and ipratropium. In the guinea-pig isolated trachea, the time (t1/2) necessary for a contractile response to carbachol (0.3 microM) to return to 50% recovery after washout o...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706724
更新日期：2006-06-01 00:00:00
abstract：:1 Thermic oedema induced by heating rat paws at 46.5 degrees C was potentiated by local injection of adrenaline, noradrenaline or high doses of isoprenaline. The pro-inflammatory effect of sympathomimetic amines was antagonized by phenoxybenzamine or phentolamine but not by propranolol.2 The subcutaneous space of heat...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1974.tb08568.x
更新日期：1974-02-01 00:00:00
abstract：:1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702389
更新日期：1999-02-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Exposure to an acute stress inhibits gastric emptying and stimulates colonic transit via central neuropeptide Y (NPY) pathways; however, peripheral involvement is uncertain. The anxiogenic phenotype of NPY(-/-) mice is gender-dependent, raising the possibility that stress-induced gastrointestinal...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2012.01939.x
更新日期：2012-08-01 00:00:00
abstract：:1.--The small protein Bv8, isolated from the amphibian skin, belongs to a novel family of secreted proteins linked to several biological effects. We describe the expression of Bv8/prokineticins and their receptors in mouse macrophages, and characterize their proinflammatory activities. 2.--The rodent analogue of Bv8, ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706467
更新日期：2006-01-01 00:00:00
abstract：:1. Adult male rats were treated with propranolol (2.0 mg kg-1 day-1 i.p.), pindolol (0.2 mg kg-1 day-1 i.p.) or 0.9% NaCl day-1 i.p. and exposed to +4 degrees C for 42 days, or treated with 0.9% NaCl day-1 i.p. and kept at +23 degrees C for 42 days. They were weighed once a week, when a 24 h urine sample was also coll...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb12988.x
更新日期：1990-04-01 00:00:00
abstract：:1. The present study shows the effects of imipramine in a single dose (10 mg kg(-1), p.o.) or following repeated (14 days, twice a day) treatment on the level of mRNA coding for D2 dopamine receptors in the rat caudate putamen (CP). Repeated administration of imipramine resulted in the increase of the level of mRNA co...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701681
更新日期：1998-03-01 00:00:00
abstract：:1. Voltage-operated calcium channel (VOCC) antagonists are effective antihypertensive and antianginal agents but they also depress myocardial contractility. 2. We compared four L-type calcium channel antagonists, felodipine, nifedipine, amlodipine and verapamil and a relatively T-type selective calcium channel antagon...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702045
更新日期：1998-09-01 00:00:00
abstract：:1. We have characterized the human smooth muscle endothelin converting enzyme (ECE) present in the media of the endothelium-denuded human umbilical vein preparation. 2. Endothelin-1 (ET-1) and ET-2 were potent constrictors of umbilical vein with EC50 values of 9.2 nM and 29.6 nM, respectively. ET-1 was at least 30 tim...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701564
更新日期：1997-12-01 00:00:00
abstract：:1. The effects of dimethothiazine have been studied on the response of afferent fibres from primary and secondary endings of muscle spindles in the soleus muscle of the decerebrate cat during stretching of the muscle under controlled conditions.2. Dimethothiazine in doses of 1 to 4 mg/kg intravenously reduced the disc...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1970.tb10360.x
更新日期：1970-07-01 00:00:00
abstract：BACKGROUND AND PURPOSE:While remifentanil can be used either during labour or fetal surgery, more should be known about the transplacental transfer of this opioid. The aim of this study was to investigate the placental transfer and haemodynamic effects of remifentanil after i.v. administration to pregnant ewes. EXPERI...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2010.00783.x
更新日期：2010-12-01 00:00:00
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：BACKGROUND AND PURPOSE:Gut microbiota plays an important role in type 2 diabetes mellitus (T2DM) progression. From our previous work N-(4-Hydroxyphenethyl)-3-mercapto-2-methylpropanamide (HMPA) is a potential T2DM drug. We evaluated the effect of HMPA on gut microbiota and studied the molecular mechanism underlying HMP...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.15338
更新日期：2020-12-07 00:00:00
abstract：:1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused alb...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1991.tb09844.x
更新日期：1991-07-01 00:00:00
abstract：:1 The binding of [3H]-muscimol, a potent gamma-aminobutyric acid (GABA) receptor agonist, to crude membrane preparations of bovine retina was studied, using a filtration method to isolate membrane-bound ligand. 2 Specific binding was found to be saturable and occurred at two binding sites with affinity constants of 4....
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1980.tb10934.x
更新日期：1980-01-01 00:00:00
