The Experts below are selected from a list of 51 Experts worldwide ranked by ideXlab platform
Derek N. Middlemiss - One of the best experts on this subject based on the ideXlab platform.
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Stereoselective actions of the isomers of Metitepine at 5-HT1D receptors in the guinea pig brain.
Neuropharmacology, 1993Co-Authors: Lynn O. Wilkinson, Lynda M. Hawkins, Margaret S. Beer, Marcel Hibert, Derek N. MiddlemissAbstract:Abstract The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT receptor antagonist Metitepine at the 5-HT1D binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl [125]iodotyrosinamide ([125I]GTI), and at the terminal 5-HT autoreceptor in guinea pig frontal cortex, a proposed model of 5-HT1D receptor activation. The pharmacological specificity of the [125I]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT1D recognition site labelled with [3H]5-HT. The (+) isomer of Metitepine displaced [125I]GTI binding with a lower affinity (64 nM) than did the (−) isomer (18 nM), which was equiactive with the racemic mixture. The (−) isomer of Metitepine was more effective than the (+) isomer at attenuating the inhibitory effects of 5-HT and sumatriptan at the guinea pig terminal 5-HT autoreceptor; the apparent pA2 of the (−) isomer was 8.0 (sumatriptan) and 7.7 (5-HT) while the apparent pA2 of the (+) isomer was 7.1 (sumatriptan) and 6.8 (5-HT). The (−) isomer was more effective than the (+) isomer at enhancing stimulated [3H]5-HT release. These findings support the identification of the guinea pig 5-HT terminal autoreceptor as a 5-HT1D receptor and reinforce the species homology between the 5-HT1B and 5-HT1D receptors.
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Metitepine distinguishes two receptors mediating inhibition of [^3H]-5-hydroxytryptamine release in guinea pig hippocampus
Naunyn-Schmiedeberg's Archives of Pharmacology, 1992Co-Authors: Lynn O. Wilkinson, Derek N. MiddlemissAbstract: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-HT_1D 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 pA_2 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 pA_2 = 6.7),and this was similar to the ability of Metitepine to attenuate the effects of 5-CT (apparent pA_2 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.
David J. Heal - One of the best experts on this subject based on the ideXlab platform.
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Opposing roles for 5-HT1B and 5-HT3 receptors in the control of 5-HT release in rat hippocampus in vivo
British journal of pharmacology, 1992Co-Authors: Keith F. Martin, Serina D Hannon, Ian Phillips, David J. HealAbstract:1. Intracerebral microdialysis was used to determine whether 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of rats anaesthetized with chloral hydrate was modulated by 5-HT3 receptors. 2. It was confirmed that 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a selective 5-HT1B receptor agonist, decreased 5-HT release in a dose- and concentration-related manner when administered i.p. (1 and 5 mg kg-1) or via the dialysis probe (0.1 and 1 microM) respectively. The effect of RU 24969 infusion (1 microM) was attenuated by concurrent infusion of Metitepine (10 microM) into the hippocampus. 3. When infused into the hippocampus for 15 min, the selective 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; 0.1- 10 microM) increased dialysate 5-HT levels in a concentration-related manner; an effect which was abolished by concurrent infusion of 3-tropanyl-3,5-dichlorobenzoate (1 microM, MDL 72222), a selective 5-HT3 antagonist. 4. MDL 72222 had no effects on hippocampal 5-HT release when administered via the dialysis probe (1 or 10 microM). 5. The data show that 5-HT3 and 5-HT1B receptors have opposing roles in the control of 5-HT release in the hippocampus, with 5-HT3 receptors facilitating and 5-HT1B receptors inhibiting 5-HT efflux, respectively. They also indicate that the facilitatory 5-HT3 receptors are not tonically activated.
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Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants.
British journal of pharmacology, 1992Co-Authors: Keith F. Martin, Ian Phillips, Mitchell Hearson, M.r. Prow, David J. HealAbstract:1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and Metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 6. Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A autoreceptors. They also indicate that the response involves D2 receptors.The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.
Lynn O. Wilkinson - One of the best experts on this subject based on the ideXlab platform.
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Stereoselective actions of the isomers of Metitepine at 5-HT1D receptors in the guinea pig brain.
Neuropharmacology, 1993Co-Authors: Lynn O. Wilkinson, Lynda M. Hawkins, Margaret S. Beer, Marcel Hibert, Derek N. MiddlemissAbstract:Abstract The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT receptor antagonist Metitepine at the 5-HT1D binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl [125]iodotyrosinamide ([125I]GTI), and at the terminal 5-HT autoreceptor in guinea pig frontal cortex, a proposed model of 5-HT1D receptor activation. The pharmacological specificity of the [125I]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT1D recognition site labelled with [3H]5-HT. The (+) isomer of Metitepine displaced [125I]GTI binding with a lower affinity (64 nM) than did the (−) isomer (18 nM), which was equiactive with the racemic mixture. The (−) isomer of Metitepine was more effective than the (+) isomer at attenuating the inhibitory effects of 5-HT and sumatriptan at the guinea pig terminal 5-HT autoreceptor; the apparent pA2 of the (−) isomer was 8.0 (sumatriptan) and 7.7 (5-HT) while the apparent pA2 of the (+) isomer was 7.1 (sumatriptan) and 6.8 (5-HT). The (−) isomer was more effective than the (+) isomer at enhancing stimulated [3H]5-HT release. These findings support the identification of the guinea pig 5-HT terminal autoreceptor as a 5-HT1D receptor and reinforce the species homology between the 5-HT1B and 5-HT1D receptors.
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Metitepine distinguishes two receptors mediating inhibition of [^3H]-5-hydroxytryptamine release in guinea pig hippocampus
Naunyn-Schmiedeberg's Archives of Pharmacology, 1992Co-Authors: Lynn O. Wilkinson, Derek N. MiddlemissAbstract: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-HT_1D 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 pA_2 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 pA_2 = 6.7),and this was similar to the ability of Metitepine to attenuate the effects of 5-CT (apparent pA_2 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.
Yasuo Shimo - One of the best experts on this subject based on the ideXlab platform.
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Investigation into the 5-hydroxytryptamine-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon.
British journal of pharmacology, 1996Co-Authors: Shuichi Kojima, Yasuo ShimoAbstract:1. The aim of this study was to characterize the receptors mediating the atropine-resistant neurogenic contraction to 5-hydroxytryptamine (5-HT) in the longitudinal muscle of the guinea-pig proximal colon and to determine the type of tachykinin receptors involved in the contractile response to 5-HT by the use of selective antagonists. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM), ketanserin (0.1 microM) and indomethacin (3 microM), 5-HT (0.01-3 microM) produced concentration-dependent neurogenic contractions of colonic strips and at 0.3 microM produced a maximal effect (pEC50 = 7.39 +/- 0.09, n = 18). The 5-HT4 receptor stimulant, 5-methoxytryptamine (5-MeOT, 0.03-10 microM) also produced neurogenic contractions with similar maximum effect to those of 5-HT (pEC50 = 6.89 +/- 0.16). 3. The 5-HT4 receptor antagonist, DAU 6285 (3 microM) shifted the concentration-response curves to both 5-HT and 5-MeOT to the right without significant depression of the maximum, but the 5-HT1/5-HT2 receptor antagonist, Metitepine (0.1 microM) and the 5-HT3 receptor antagonist, ondansetron (0.3 microM) had no effect on the control curves to 5-HT and 5-MeOT. 4. The selective NK1 receptor antagonist, FK 888 (1 microM) markedly attenuated the contractions to 5-HT and 5-MeOT. In contrast, the selective NK2 receptor antagonist, SR 48968 (10 nM) and the selective NK3 receptor antagonist, SR 142801 (10 nM) had no effect on the contractions to 5-HT and 5-MeOT. 5. These results indicate that the 5-HT-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon is due to activation of 5-HT4 receptors, presumably located on excitatory motor neurones, innervating the longitudinal muscle. The contraction evoked by activation of the 5-HT4 receptors is mediated primarily via NK1 receptors but not NK2 or NK3, suggesting that the 5-HT4 receptor-mediated contraction is evoked indirectly via tachykinin release from tachykinin-releasing excitatory neurones.
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investigation into the 5 hydroxytryptamine induced relaxation of the circular smooth muscle of guinea pig stomach fundus
European Journal of Pharmacology, 1992Co-Authors: Shuichi Kojima, Rika Ishizaki, Yasuo ShimoAbstract:Abstract The 5-HT receptor that mediates relaxation of circular muscle strips of the guinea-pig stomach fundus under resting tone was investigated. Concentration-dependent relaxation was obtained in the presence of atropine (0.2 μM) with 5-hydroxytryptamine (5-HT) (apparent mean pEC50 value, 5.27), 5-carboxamidotryptamine (7.35),-methoxytryptamine (4.98) and 5-methyltryptamine (4.58). 1-(m-Trifluoromethyl-phenyl)piperazine and 8-hydroxy-2-(di-n-propylamino)tetralin acted as partial agonists while 2-methyl-5-hydroxytryptamine, α-methyl-5-hydroxytryptamine, sumatriptan, metoclopramide and cisapride had little or no effect on the guinea-pig stomach fundus. The concentration-response curve for 5-HT was not affected by tetrodotoxin (0.3 μM), guanethidine (5 μM) or indomethacin (2 μM), suggesting that the relaxation is non-neuronal in origin and is independent of the release of catecholamines or prostanoids. The non-selective 5-HT receptor antagonist, Metitepine (0.03–0.1 μM), the 5-HTIC/5-HT2 receptor antagonists, mianserin (0.3–1 μM), pizotifen (0.3–1 μM), ketanserin (3–10 μM), and the 5-HT1A/5-HT2 receptor antagonist, spiperone (3 μM), shifted the concentration-response curves for 5-HT to the right. A 5-HT3 receptor antagonist, ICS205-930 (1 μM), propranolol (1 μM) and phentolamine (1 μM) failed to block the 5-HT-induced relaxation. In conclusion, the results found with agonists and antagonists are compatible with the view that a 5-HT1-like receptor is involved in 5-HT-induced direct relaxation of circular muscle of guinea-pig stomach fundus.
Leslie B Vosshall - One of the best experts on this subject based on the ideXlab platform.
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small molecule drug screening in drosophila identifies the 5ht2a receptor as a feeding modulation target
Scientific Reports, 2013Co-Authors: Gabriel Gasque, Stephen Conway, Juan Huang, Yi Rao, Leslie B VosshallAbstract:Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist Metitepine as a potent anorectic drug. Using cell-based assays we show that Metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by Metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake.