Abstract：
BACKGROUND AND PURPOSE:Melanin-concentrating hormone receptor 1 (MCH1 receptor) antagonists are being considered as anti-obesity agents. The present study reports a new class of MCH1 receptor antagonists with an 8-methylquinoline scaffold. The molecular mechanism of MCH1 receptor blockade by these antagonists was examined. EXPERIMENTAL APPROACH:The pharmacological properties of the 8-methylquinolines as exemplified by MQ1 were evaluated by use of multiple biophysical and cell-based functional assays. KEY RESULTS:Multiple signalling pathways for Gαi and Gαq , and β-arrestin were inhibited by MQ1. Furthermore, MQ1 produced an insurmountable antagonism, causing a rightward shift of the curve for concentration-dependent binding of MCH along with a progressive reduction of the maximal response. The dissociation kinetics for MQ1 were determined from washout experiments as well as by affinity selection-MS. In short, MQ1 was shown to be a slowly dissociating reversible MCH1 receptor blocker with a low Koff value. CONCLUSION AND IMPLICATIONS:This is the first time that a slowly dissociating negative allosteric modulator of the MCH1 receptor has been demonstrated to inhibit the numerous signalling pathways of this receptor. The characteristics of MQ1 are superior and distinct from previously reported MCH1 receptor antagonists, making members of this chemotype attractive as drug candidates.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Sakurai T,Ogawa K,Ishihara Y,Kasai S,Nakayama Mdoi
10.1111/bph.12529subject
Has Abstractpub_date
2014-03-01 00:00:00pages
1287-98issue
5eissn
0007-1188issn
1476-5381journal_volume
171pub_type
杂志文章abstract：BACKGROUND AND PURPOSE:The endocannabinoid system and the cannabinoid CB(1) receptor have been identified in human sperm, and it is well known that endocannabinoids have pronounced adverse effects on male and female reproduction. In order to elucidate further the pathophysiological role of the endocannabinoid system in...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2009.00570.x
更新日期：2010-02-01 00:00:00
abstract：:The effect of docosahexaenoic acid (DHA) on nitric oxide (NO) production and inducible NO synthase (iNOS) expression induced by interleukin (IL)-1beta, and whether the effect of DHA is related to its effect on mitogen-activated protein kinase (MAPK) activation were investigated in cultured rat vascular smooth muscle c...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704768
更新日期：2002-06-01 00:00:00
abstract：:1. The effects of the spasmogenic agents, carbachol (CCh), histamine, 5-hydroxytryptamine (5-HT) and 9,11-epithio-11,12-methano-thromboxane A2 (STA2) were investigated on smooth muscle tissues of the dog trachea. 2. CCh (10 microM) produced a larger contraction than high K (128 mM), 10 microM histamine, 5-HT or STA2. ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb12049.x
更新日期：1990-05-01 00:00:00
abstract：:1 The butyrophenone tranquilizer, azaperone, was administered intramuscularly, at dose levels of 0.4 and 0.8 mg/kg, to ponies and its effects on cardiovascular and respiratory functions assessed. 2 Arterial blood pH, CO2 tension (PaCO2) and O2 tension (PaO2) remained relatively constant throughout the course of action...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1976.tb07637.x
更新日期：1976-03-01 00:00:00
abstract：:1. We have evaluated the selectivity of ketoprofen and two novel nonsteroidal anti-inflammatory drugs, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulphonamide (NS-398) and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indano ne (L-745,337), in inhibiting the cyclo-oxygenase activity of prostaglandin endoperoxide s...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1995.tb15091.x
更新日期：1995-11-01 00:00:00
abstract：:1. gamma-Aminobutyric acid (GABA) was applied by the 'concentration clamp' technique to isolated neurones of Aplysia. GABA induced a chloride current (ICl) due to activation of a single class of chloride-channel. 2. The concentration-response curve for the peak ICl gave an apparent dissociation constant of 6.4 X 10(-5...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11718.x
更新日期：1988-11-01 00:00:00
abstract：:1. The effects of chronic dietary supplementation with omega 3 polyunsaturated fatty acids on endothelium-dependent relaxations were examined in isolated coronary microvessels of the pig. 2. Animals were maintained for four weeks with or without dietary supplementation of purified eicosapentaenoic acid (3.5 g daily) a...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11755.x
更新日期：1988-12-01 00:00:00
abstract：:1. The purpose of the present study was to determine the myocardial cytoprotective efficacy of azapropazone (AZA) and its potential site of action on neutrophil infiltration into reperfused/ischaemic myocardium with or without in vivo activation of neutrophils in rabbits. 2. AZA, 100 mg kg-1, was administered i.v. 10 ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb15813.x
更新日期：1990-06-01 00:00:00
abstract：:1. Increased calcium (Ca2+) influx has been incriminated as a potential pathological mechanism in the chronic skeletal muscle degeneration exhibited by Duchenne muscular dystrophy (DMD) patients. We have studied the influence of the glucocorticoid alpha-methylprednisolone (PDN), the only drug known to have a beneficia...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1995.tb15930.x
更新日期：1995-12-01 00:00:00
abstract：:Authentic nitric oxide (NO; 0.1 - 10 micromoles) caused transient, dose-dependent relaxation of phenylephrine-induced tone without changing membrane potential in mesenteric arteries. Larger doses, above 10 micromoles, did not evoke more relaxation (maximal relaxation to 150 micromoles NO in denuded arteries, 69+/-7%, ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704127
更新日期：2001-07-01 00:00:00
abstract：:1. The present study characterizes and classifies alpha 1-adrenoceptor-mediated vasoconstriction in the isolated perfused kidney of rat using quantitative receptor pharmacology and compares the results to radioligand binding studies (made in cloned alpha 1-adrenoceptor subtypes, native alpha 1A-adrenoceptors in submax...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1995.tb15875.x
更新日期：1995-05-01 00:00:00
abstract：:1. 5-Hydroxytryptamine (5-HT) stimulates active sodium transport and decreases the passive mucosal to serosal chloride permeability across frog skin. The relative importance of the different regions of the 5-HT molecule in the mediation of these responses has been studied using a range of structurally related compound...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1979.tb07867.x
更新日期：1979-04-01 00:00:00
abstract：:1. 2-2' Pyridylisatogen tosylate (PIT) (greater than 2.5 muM) relaxed the guinea-pig isolated taenia caeci by an unknown mechanism. 2. With higher concentrations of PIT (greater than 12.5 muM) subsequent applications of adenosine 5'-triphosphate (ATP) (2-600 muM) revealed a blockade of the ATP receptors. The antagonis...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1975.tb07397.x
更新日期：1975-04-01 00:00:00
abstract：:1. A series of 5-hydroxytryptamine (5-HT) receptor agonists including 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced little or no contraction of rabbit isolated mesenteric arteries under resting tone conditions, even at concentrations up to 10(-4) M. 2. When the same agonists were retested in mesenteric...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1995.tb13228.x
更新日期：1995-01-01 00:00:00
abstract：:1. Previous work from our laboratory has shown that cannabis induces aggressive behaviour in rats that have been deprived of rapid eye movement (REM) sleep. It was suggested that this effect was related to brain catecholamines, with dopamine playing an agonist role and noradrenaline an inhibitory one. The present pape...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1977.tb08429.x
更新日期：1977-11-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood-brain barrier (BBB) and detract from the possible cl...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2011.01290.x
更新日期：2011-07-01 00:00:00
abstract：:The effect of leukaemia inhibitory factor (LIF) in modulating cholinergic and sensory nerve function was examined using guinea-pig tracheal explants. Specific LIF receptors (LIFR) were immunolocalized to both cholinergic and sensory nerves. Release of SP in culture was not influenced by LIF. Similarly, maximum contrac...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703415
更新日期：2000-07-01 00:00:00
abstract：:1. In the anaesthetized dog bombesin had a potent antidiuretic effect, and sometimes arrested urine flow completely. Threshold doses, by i.v. infusion, were of the order of 0.5-1 (ng/kg)/minute. Antidiuresis was the result of a reduction in glomerular filtration rate provoked by a fall in intraglomerular hydrostatic p...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1973.tb08352.x
更新日期：1973-07-01 00:00:00
abstract：:1 The effects of prostaglandin (PGE(1)), following local administration during different phases of developing sponge-induced granulomata, were studied in normal and essential fatty acid deficient (EFAD) rats.2 In normal rats, a single dose of 1 mug PGE(1) on implantation (day 1) increased exudate production without al...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1979.tb07852.x
更新日期：1979-03-01 00:00:00
abstract：:1. Tyrosine kinases have been proposed as regulators of voltage-operated calcium channels. The effects of a range of structurally different inhibitors of protein tyrosine kinases (PTK) were examined on voltage-operated calcium channel currents (I(Ba)) and pp60(c-src) kinase (c-src) activity in vitro. 2. I(Ba) was meas...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703186
更新日期：2000-04-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Transforming growth factor beta1 (TGFbeta1) is generated in atherosclerotic and injured vessel walls. We examined whether the endothelial-to-mesenchymal transdifferentiation induced by TGFbeta1 affects endothelial functions. EXPERIMENTAL APPROACH:Bovine aortic endothelial cells (BAECs) were trea...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706883
更新日期：2006-10-01 00:00:00
abstract：:1. The convulsive effects of leptazol in the rat are potentiated by prior treatment with dexamphetamine.2. An intact dopamine synthesis is necessary for the potentiation of the convulsive action of leptazol.3. An intact noradrenaline synthesis is not necessary for this action of amphetamine, as long as the dopamine sy...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1969.tb09526.x
更新日期：1969-09-01 00:00:00
abstract：BACKGROUND AND PURPOSE:A fluorinated derivative (2F-MT-45) of the synthetic μ-opioid receptor agonist MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) was recently identified in a seized illicit tablet. While MT-45 is a Class A drug, banned in a number of countries, nothing is known about the pharmacology of 2F-MT-...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.15064
更新日期：2020-08-01 00:00:00
abstract：:1. The benzodiazepine site of the alpha 6 beta 2 gamma 2 subtype of gamma-aminobutyric acidA (GABAA) receptors is distinguishable from that of the alpha 1 beta 2 gamma 2 subtype by its inability to interact with classical benzodiazepines (i.e., diazepam) and its agonistic response to Ro 15-1788, which behaves as an an...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0700931
更新日期：1997-02-01 00:00:00
abstract：:Prostate cancer is the second most common malignancy in men and androgen deprivation therapy is the first-line therapy. However, most cases will eventually develop castration-resistant prostate cancer after androgen deprivation therapy treatment. Enzalutamide is a second-generation androgen receptor antagonist approve...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.15300
更新日期：2020-11-05 00:00:00
abstract：:1. The action of the non-steroidal anti-inflammatory drugs (NSAID), sodium salicylate, aspirin, phenylbutazone and indomethacin was investigated on the migration of human polymorphonuclear cells (PMNs) and lymphocytes, using the system of migration of leucocytes from glass capillary tubes. 2. All NSAID produced a dose...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：
更新日期：1978-11-01 00:00:00
abstract：:1. In the present study we tested the hypothesis that insulin-like growth factor-1 (IGF-1) modulates resting chloride conductance (G(Cl)) of rat skeletal muscle by activating a phosphatase and that the chloride channel, based on the activity of phosphorylating-dephosphorylating pathways, has different sensitivity to s...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702107
更新日期：1998-10-01 00:00:00
abstract：:The ability of chemically detoxified E. coli endotoxins and membrane-active agents to modify the toxicity of native E. coli endotoxin in vivo was examined. The time- and dose-dependent increase in plasma acid phosphatase activity following toxin administration to rats provided a convenient quantitative measure of in v...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1983.tb11015.x
更新日期：1983-06-01 00:00:00
abstract：:1. Caffeine has been widely used as a pharmacological tool to evaluate Ca(2+) release from the sarcoplasmic reticulum in isolated smooth muscle cells. However, in nervous tissue this drug also causes neurotransmitters release, which might cause additional effects when smooth muscle strips are evaluated. To assess this...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705348
更新日期：2003-07-01 00:00:00
abstract：:1. The role of both exogenously administered and endogenously generated bradykinin (BK) on LPS-induced eosinophil accumulation in the mice pleural cavity was investigated by means of treatment with BK selective receptor agonists/antagonists and captopril. 2. Intrathoracic (i.t.) injection of LPS (250 ng cavity(-1)) in...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702567
更新日期：1999-05-01 00:00:00
