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  • 1
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of medicinal chemistry 35 (1992), S. 2025-2033 
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 7 (2001), S. 0 
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1′-ethyl-5-(2′-methyl-4′-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4′-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT1B receptors (pKi= 8.2) and displays 80 or more fold selectivity for the human 5-HT1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT1B receptors SB-236057-A displayed inverse agonism (pA2= 8.9) using [35S]GTPγS binding, and silent antagonism (pA2= 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [3H]5-HT release from electrically stimulated guinea pig and human cortical slices.In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration.SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT1B subtype. It appears that acute 5-HT1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 600 (1990), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 267 (1977), S. 289-290 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Specific binding of 3H-5-HT was measured by the method of Bennett and Snyder4. The whole brain (minus the cerebellum) of a freshly killed Alderley Park rat (250-350 g) was rapidly removed and homogenised in 30 ml of ice-cold 0.32 M sucrose with five passes of an air-driven glass-Teflon homogeniser. ...
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1912
    Keywords: 5-HT autoreceptors ; Presynaptic receptors ; Rat frontal cortex ; K+ depolarization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments have been carried out to provide direct evidence for the proposed presynaptic 5-HT autoreceptor agonist activity of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) a compound with selectivity for the 5-HT1A subtype of the 5-HT1 binding site. Rat brain frontal cortex slices were preincubated with [3H] 5-hydroxytryptamine and continuously stimulated with Krebs solution containing paroxetine and elevated K+ ions (25 mmol/l). The elevated efflux of tritium caused by exposure to K+ Krebs was inhibited in a dose related manner by 5-hydroxytryptamine and this inhibition was attenuated in the presence of quipazine and methiothepin. In slices of the rat frontal cortex, 8-OH-DPAT was without agonist or antagonist activity at the 5-HT autoreceptor at concentrations up to 1 μmol/l. Higher concentrations caused an increase in basal efflux of tritium. 8-OH-DPAT (1 μmol/l) was also without inhibitory activity in the piriform cortex, striatum and the hippocampus. These experiments have therefore failed to provide direct evidence for agonist activity of 8-OH-DPAT at the 5-HT autoreceptor and alternative explanations must be sought for its biochemical and behavioural effects in vivo. Moreover, the fact that 8-OH-DPAT is inactive at the autoreceptor at concentrations selective for the 5-HT1A recognition site suggests that this subtype of the 5-HT1A binding site may not correspond to the 5-HT autoreceptor.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-2072
    Keywords: Key words Sauvagine ; Urotensin I ; Corticotropin-releasing factor ; Urocortin ; Hypophagia ; Anxiogenesis ; Hyperactivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study determined the behavioural effects of the corticotropin releasing factor (CRF)-related peptides, human/rat CRF (h/rCRF), ovine CRF (oCRF), sauvagine (SAUV), urotensin I (UT) and the recently discovered neuropeptide, rat urocortin (rUCN). All of the peptides dose-dependently increased motor activity in a familiar environment and reduced feeding in hungry rats. There was no apparent relationship between potency/affinity at CRF2 receptors and effects in these two tests. In a comparison of h/rCRF and rUCN upon discrete spontaneous behaviours, both peptides (3.0 μg ICV) increased activity and grooming, induced a fore-paw tremor and reduced the incidence of motionlessness. However, h/rCRF reduced motionlessness to a greater extent and was a more potent inducer of defaecation, weight loss, oral movements and fore-paw tremor than rUCN. In the elevated X maze, both h/rCRF and rUCN (1.0 μg ICV) had anxiogenic-like effects upon behaviour. In contrast, h/rCRF (1.0 μg ICV), but not rUCN (1.0–10 μg ICV) increased the startle response to an acoustic stimulus. In summary, all the CRF-related peptides increased motor activity and reduced feeding in rats in a similar manner and both rUCN and h/rCRF induced anxiogenesis. However, there were some behavioural differences between rUCN and h/rCRF which require further study. Further pharmacological investigation of the role of CRF receptor subtypes requires the use of subtype selective antagonists.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 345 (1992), S. 696-699 
    ISSN: 1432-1912
    Keywords: Serotonin ; 5-HT1D-receptor ; Autoreceptor ; Guinea pig ; Hippocampus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Inhibition of [3H]-5-hydroxytryptamine ([3H]-5-HT) release from guinea pig brain slices via activation of the terminal 5-HT autoreceptor has previously been characterised as a model of 5-HT1D receptor activation, based on the rank potencies of a range of agonists, and the potent antagonism of the inhibitory effects of 5-HT by metitepine. The present study uses this model, in slices of the guinea pig hippocampus, to examine the antagonist potency of metitepine against the 5-HT receptor agonists sumatriptan, 5-carboxamidotryptamine (5-CT) and 5-HT Addition of metitepine to the perfusion buffer (30, 300 and 1000 nmol/l) significantly shifted the concentration-response curve to 5-HT, producing a Schild slope of 1.1, and a pA2 value of 7.6. However, the ability of metitepine to antagonise the effects of sumatriptan or 5-CT in this model was less marked. A clear-cut shift in the concentration-response curve to sumatriptan was only achieved at1000 nmol/l metitepine (apparent pA2 = 6.7),and this was similar to the ability of metitepine to attenuate the effects of 5-CT (apparent pA2 7.0 at 300 nmol/l and 6.7 at 1000 nmol/l). These findings suggest heterogeneity in the receptor mediating inhibition of [3H]-5-HT release in guinea pig hippocampus.
    Type of Medium: Electronic Resource
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