5-Carboxamidotryptamine

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Christian Waeber - One of the best experts on this subject based on the ideXlab platform.

  • Putative 5-ht5 receptors: localization in the mouse CNS and lack of effect in the inhibition of dural protein extravasation.
    Annals of the New York Academy of Sciences, 1998
    Co-Authors: Christian Waeber, René Hen, Régis Grailhe, Michael A. Moskowitz
    Abstract:

    Putative 5-ht5 receptor binding sites were visualized by in vitro autoradiography using [125I]LSD (in the presence of clozapine and spiperone) or [3H]5-Carboxamidotryptamine (in the presence 8-OH-DPAT, GR127935 and spiperone). Under these conditions, no [3H]5-Carboxamidotryptamine labeling was detected in the brain of mice lacking the gene encoding the putative 5-ht5a receptor (knockout mice), whereas intermediate densities of binding sites were seen in the olfactory bulb and neocortex of wild-type mice. [125I]LSD labeled the same areas as [3H]5-Carboxamidotryptamine in wild-type mice. High densities of [125I]LSD binding sites were observed in the medial habenula of wild type and knockout mice. 5-CT competed for [125I]LSD binding sites with an affinity of 2 nM in the olfactory bulb and neocortex of wild-type mice and an affinity of 30 nM in the habenula of knockout mice, suggesting that habenular labeling might be accounted for by putative 5-ht5b receptors. In the presence of 5'-guanylylimidodiphosphate, 5-CT displaced [125I]LSD from putative 5-ht5a and 5-ht5b sites with a 6-times and 3-times lower affinity, respectively, suggesting that both receptor subtypes are coupled to G proteins in brain. We also studied the inhibitory effect of 5-CT on dural neurogenic inflammation in knockout mice. In wild type mice, 3 ng/kg 5-CT inhibited dural protein extravasation by 60%. A similar effect was observed in knockout mice, even in the presence of the 5-HT1B receptor antagonist GR127935. These results suggest that the inhibitory effects of 5-CT are not mediated by a site with the characteristics of the putative 5-ht5 receptor.

  • The 5-HT1D receptor antagonist GR-127,935 prevents inhibitory effects of sumatriptan but not CP-122,288 and 5-CT on neurogenic plasma extravasation within guinea pig dura mater.
    Neuropharmacology, 1997
    Co-Authors: F. M. Cutrer, Michael A. Moskowitz, Christian Waeber
    Abstract:

    Abstract The aim of this study was to examine whether GR-127,935, a 5-HT1B/1D receptor antagonist, blocks the inhibitory effects of sumatriptan, CP-122,288 and 5-Carboxamidotryptamine (5-CT) on plasma protein extravasation, within guinea pig and rat dura mater, following electric stimulation of the trigeminal ganglion. Binding studies first established that GR-127,935 shows a 500-fold selectivity for 5-HT1D binding sites (labeled by [3H]L-694,247) versus 5-HT1F binding sites (labeled by 3H]sumatriptan in the presence of 50 nM 5-Carboxamidotryptamine) in guinea pig forebrain homogenates (pKD ± SD = 7.0 ± 0.2 at 5-HT1F sites and 9.7 ± 0.1 at 5-HT1D sites). In guinea pigs, GR-127,935 showed partial agonist activity and inhibited dural plasma protein extravasation. Increasing doses of GR-127,935 reversed the effect of sumatriptan, but did not affect the action of 5-CT and CP-122,288 (at a dose as high as 2 μmol/kg). Sumatriptan, CP 122,288 and 5-CT dose-responsively inhibited plasma protein extravasation. At a dose of 2 μmol/kg (but not at 0.2 μmol/kg), GR-127,935 right-shifted the dose-response curve of sumatriptan. No significant rightward shift was observed in the dose-response of CP-122,288 and 5-CT. In rats, GR-127,935 did not show any significant partial agonist activity. A dose of 0.2 μmol/kg was sufficient to right-shift the dose-response curve of sumatriptan. These data suggest that sumatriptan inhibits neurogenic inflammation via 5-HT1Dα receptors in guinea pigs and 5-HT1Dβ (5-HT1B) receptors in rats. Additional receptor subtypes are likely to be involved in the inhibition of plasma extravasation by CP-122,288 and 5-CT. Pertussis toxin reduced the inhibitory effects of both sumatriptan and 5-CT, but not of muscimol, known to act at GABAA receptors. These results suggest that 5-CT, as well as sumatriptan, act at a receptor linked to an inhibitory G-protein. © 1997 Elsevier Science Ltd. All rights reserved.

  • Autoradiographic visualisation of [3H]5-Carboxamidotryptamine binding sites in the guinea pig and rat brain.
    European journal of pharmacology, 1995
    Co-Authors: Christian Waeber, Michael A. Moskowitz
    Abstract:

    Abstract We have investigated the distribution of [3H]5-Carboxamidotryptamine ([3H]5-CT) binding sites by in vitro autoradiography on sections of guinea-pig and rat brain. In saturation studies, the ligand recognised a saturable, homogeneous population of binding sites with an affinity ranging from 0.19–0.45 nM depending on the region. The labelling pattern was heterogeneous, and the displacement pattern with different competing drugs selective for different 5-HT receptor subtypes was complex. [3H]5-CT appeared to label 5-HT 1B 5-HT 1D sites in the substantia nigra, globus pallidus and caudate/putamen, as the binding in these regions was displaced by the 5-HT 1B 1D receptor selective agents sumatriptan, CP-122,288 and GR-127,935. In the hippocampus and lateral septum, the very dense [3H]5-CT binding was displaced with high affinity by the 5-HT1A receptor selective agonist 8-hydroxy-dipropylaminotetralin ((±)-8-OH-DPAT), dihydroergotamine and 5-HT. In contrast the affinity of the 5-HT1 receptor antagonists spiperone and methiothepine was much lower than their previously published potency at 5-HT1A receptors. The affinity of agonists, taken together with the fact that the distribution of these [3H]5-CT sites overlaps that of [3H]8-OH-DPAT binding sites in serial sections, suggest that these sites correspond to 5-HT1A receptors. Their atypical properties deserve further investigations. While [3H]5-CT binding at 5-HT 1B 1D sites and these atypical 5-HT1A sites was inhibited by the GTP analogue 5′-β,γ-imidotriphosphate, [3H]5-CT binding in the superficial cortical layers and in midline thalamic nuclei was insensitive to this agent. It was however displaced by low concentrations of spiperone, clozapine and methiothepine, but not by sumatriptan, CP-122,288, GR-127,935 or dihydroergotamine. This binding profile is similar to that of 5-HT7 receptors, while the spatial distribution of these sites matches the known distribution of 5-HT7 messenger RNA. We did not find evidence of [3H]5-CT labelling to 5-HT5 receptors, in spite of their reported high affinity for this ligand. It is concluded that [3H]5-CT, in the presence of selective blockers, can be used to investigate the properties of 5-HT1A, 5-HT 1B 1D and 5-HT7 receptors in the rodent brain, although further studies are required to explain the atypical features of [3H]5-CT binding in 5-HT1A receptors containing regions.

  • 5-Hydroxytryptamine receptors with a 5-HT_6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1994
    Co-Authors: Philippe Schoeffter, Christian Waeber
    Abstract:

    This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC_50 values): 5-HT (7.1) ≥ 5-methoxytryptamine (6.9) > 5-Carboxamidotryptamine (5.6) > sumatriptan (

  • 5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes.
    Naunyn-Schmiedeberg's archives of pharmacology, 1994
    Co-Authors: Philippe Schoeffter, Christian Waeber
    Abstract:

    This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) ≥ 5-methoxytryptamine (6.9) > 5-Carboxamidotryptamine (5.6) > sumatriptan (

Philippe Schoeffter - One of the best experts on this subject based on the ideXlab platform.

Nigel R. Newberry - One of the best experts on this subject based on the ideXlab platform.

  • WAY-100635 and GR127935: effects on 5-hydroxytryptamine-containing neurones.
    European journal of pharmacology, 1994
    Co-Authors: Rebecca M. Craven, David G. Grahame-smith, Nigel R. Newberry
    Abstract:

    N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) is a potent and selective 5-HT1A receptor antagonist in a slice preparation of the guinea pig dorsal raphe nucleus: the inhibitory actions on 5-HT neuronal firing of 5-hydroxytryptamine (5-HT, serotonin), 5-Carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), but not those of baclofen, were abolished by 30 nM WAY-100635. The selective 5-HT1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'- methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide (GR127935, 300 nM) did not attenuate the 5-HT induced inhibition, indicating that 5-HT1D receptors do not contribute to the inhibitory action of exogenous 5-HT on 5-HT neurones.

  • Pharmacology of the 5-hydroxytryptamine-induced depolarization of the ferret vagus nerve in vitro.
    European journal of pharmacology, 1992
    Co-Authors: Nigel R. Newberry, Clare J. Watkins, D.john M. Reynolds, R.a. Leslie, David G. Grahame-smith
    Abstract:

    Abstract Grease-gap recordings revealed that 5-hydroxytryptamine (5-HT) depolarized the ferret vagus nerve (pEC50 = 4.9). This response was mimicked by 2-methyl-5-HT and 1-phenylbiguanide, but not by 5-Carboxamidotryptamine. Paroxetine (1 μM) or ketamine (10 μM) did not potentiate the response. Ketanserin (1 μM) did not reduce the depolarization, but four 5-HT3 receptor antagonists did. It is concluded that 5-HT depolarizes the ferret vagus nerve via 5-HT3 receptors, but these receptors may differ pharmacologically from those in other species.

  • 5-HT1A receptors activate a potassium conductance in rat ventromedial hypothalamic neurones
    European journal of pharmacology, 1992
    Co-Authors: Nigel R. Newberry
    Abstract:

    Abstract The extracellularly recorded firing rate of rat ventromedial hypothalamic neurones in vitro was inhibited by 5-hydroxytryptamine (5-HT), 5-Carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, 2-methyl-5-HT was relatively ineffective. At 1 μM, spiperone and cyanopindolol antagonised the 5-CT induced inhibition, MDL 72222 (10 μM) and ketanserin (1 μM) did not. Intracellular recordings with voltage-clamp revealed that 5-HT and 5-CT evoked a tetrodotoxin-resistant outward current with a reversal potential of ca. −100 mV. 5-HT1A receptors likely activate a potassium conductance on these neurones.

Michael A. Moskowitz - One of the best experts on this subject based on the ideXlab platform.

  • Putative 5-ht5 receptors: localization in the mouse CNS and lack of effect in the inhibition of dural protein extravasation.
    Annals of the New York Academy of Sciences, 1998
    Co-Authors: Christian Waeber, René Hen, Régis Grailhe, Michael A. Moskowitz
    Abstract:

    Putative 5-ht5 receptor binding sites were visualized by in vitro autoradiography using [125I]LSD (in the presence of clozapine and spiperone) or [3H]5-Carboxamidotryptamine (in the presence 8-OH-DPAT, GR127935 and spiperone). Under these conditions, no [3H]5-Carboxamidotryptamine labeling was detected in the brain of mice lacking the gene encoding the putative 5-ht5a receptor (knockout mice), whereas intermediate densities of binding sites were seen in the olfactory bulb and neocortex of wild-type mice. [125I]LSD labeled the same areas as [3H]5-Carboxamidotryptamine in wild-type mice. High densities of [125I]LSD binding sites were observed in the medial habenula of wild type and knockout mice. 5-CT competed for [125I]LSD binding sites with an affinity of 2 nM in the olfactory bulb and neocortex of wild-type mice and an affinity of 30 nM in the habenula of knockout mice, suggesting that habenular labeling might be accounted for by putative 5-ht5b receptors. In the presence of 5'-guanylylimidodiphosphate, 5-CT displaced [125I]LSD from putative 5-ht5a and 5-ht5b sites with a 6-times and 3-times lower affinity, respectively, suggesting that both receptor subtypes are coupled to G proteins in brain. We also studied the inhibitory effect of 5-CT on dural neurogenic inflammation in knockout mice. In wild type mice, 3 ng/kg 5-CT inhibited dural protein extravasation by 60%. A similar effect was observed in knockout mice, even in the presence of the 5-HT1B receptor antagonist GR127935. These results suggest that the inhibitory effects of 5-CT are not mediated by a site with the characteristics of the putative 5-ht5 receptor.

  • The 5-HT1D receptor antagonist GR-127,935 prevents inhibitory effects of sumatriptan but not CP-122,288 and 5-CT on neurogenic plasma extravasation within guinea pig dura mater.
    Neuropharmacology, 1997
    Co-Authors: F. M. Cutrer, Michael A. Moskowitz, Christian Waeber
    Abstract:

    Abstract The aim of this study was to examine whether GR-127,935, a 5-HT1B/1D receptor antagonist, blocks the inhibitory effects of sumatriptan, CP-122,288 and 5-Carboxamidotryptamine (5-CT) on plasma protein extravasation, within guinea pig and rat dura mater, following electric stimulation of the trigeminal ganglion. Binding studies first established that GR-127,935 shows a 500-fold selectivity for 5-HT1D binding sites (labeled by [3H]L-694,247) versus 5-HT1F binding sites (labeled by 3H]sumatriptan in the presence of 50 nM 5-Carboxamidotryptamine) in guinea pig forebrain homogenates (pKD ± SD = 7.0 ± 0.2 at 5-HT1F sites and 9.7 ± 0.1 at 5-HT1D sites). In guinea pigs, GR-127,935 showed partial agonist activity and inhibited dural plasma protein extravasation. Increasing doses of GR-127,935 reversed the effect of sumatriptan, but did not affect the action of 5-CT and CP-122,288 (at a dose as high as 2 μmol/kg). Sumatriptan, CP 122,288 and 5-CT dose-responsively inhibited plasma protein extravasation. At a dose of 2 μmol/kg (but not at 0.2 μmol/kg), GR-127,935 right-shifted the dose-response curve of sumatriptan. No significant rightward shift was observed in the dose-response of CP-122,288 and 5-CT. In rats, GR-127,935 did not show any significant partial agonist activity. A dose of 0.2 μmol/kg was sufficient to right-shift the dose-response curve of sumatriptan. These data suggest that sumatriptan inhibits neurogenic inflammation via 5-HT1Dα receptors in guinea pigs and 5-HT1Dβ (5-HT1B) receptors in rats. Additional receptor subtypes are likely to be involved in the inhibition of plasma extravasation by CP-122,288 and 5-CT. Pertussis toxin reduced the inhibitory effects of both sumatriptan and 5-CT, but not of muscimol, known to act at GABAA receptors. These results suggest that 5-CT, as well as sumatriptan, act at a receptor linked to an inhibitory G-protein. © 1997 Elsevier Science Ltd. All rights reserved.

  • Autoradiographic visualisation of [3H]5-Carboxamidotryptamine binding sites in the guinea pig and rat brain.
    European journal of pharmacology, 1995
    Co-Authors: Christian Waeber, Michael A. Moskowitz
    Abstract:

    Abstract We have investigated the distribution of [3H]5-Carboxamidotryptamine ([3H]5-CT) binding sites by in vitro autoradiography on sections of guinea-pig and rat brain. In saturation studies, the ligand recognised a saturable, homogeneous population of binding sites with an affinity ranging from 0.19–0.45 nM depending on the region. The labelling pattern was heterogeneous, and the displacement pattern with different competing drugs selective for different 5-HT receptor subtypes was complex. [3H]5-CT appeared to label 5-HT 1B 5-HT 1D sites in the substantia nigra, globus pallidus and caudate/putamen, as the binding in these regions was displaced by the 5-HT 1B 1D receptor selective agents sumatriptan, CP-122,288 and GR-127,935. In the hippocampus and lateral septum, the very dense [3H]5-CT binding was displaced with high affinity by the 5-HT1A receptor selective agonist 8-hydroxy-dipropylaminotetralin ((±)-8-OH-DPAT), dihydroergotamine and 5-HT. In contrast the affinity of the 5-HT1 receptor antagonists spiperone and methiothepine was much lower than their previously published potency at 5-HT1A receptors. The affinity of agonists, taken together with the fact that the distribution of these [3H]5-CT sites overlaps that of [3H]8-OH-DPAT binding sites in serial sections, suggest that these sites correspond to 5-HT1A receptors. Their atypical properties deserve further investigations. While [3H]5-CT binding at 5-HT 1B 1D sites and these atypical 5-HT1A sites was inhibited by the GTP analogue 5′-β,γ-imidotriphosphate, [3H]5-CT binding in the superficial cortical layers and in midline thalamic nuclei was insensitive to this agent. It was however displaced by low concentrations of spiperone, clozapine and methiothepine, but not by sumatriptan, CP-122,288, GR-127,935 or dihydroergotamine. This binding profile is similar to that of 5-HT7 receptors, while the spatial distribution of these sites matches the known distribution of 5-HT7 messenger RNA. We did not find evidence of [3H]5-CT labelling to 5-HT5 receptors, in spite of their reported high affinity for this ligand. It is concluded that [3H]5-CT, in the presence of selective blockers, can be used to investigate the properties of 5-HT1A, 5-HT 1B 1D and 5-HT7 receptors in the rodent brain, although further studies are required to explain the atypical features of [3H]5-CT binding in 5-HT1A receptors containing regions.

Alberto J. Kaumann - One of the best experts on this subject based on the ideXlab platform.

  • Human S31 serotonin receptor clone encodes a 5-hydroxytryptamine1E-like serotonin receptor
    Molecular pharmacology, 1993
    Co-Authors: Thomas Gudermann, Finn Olav Levy, M. Birnbaumer, Lutz Birnbaumer, Alberto J. Kaumann
    Abstract:

    We reported recently the molecular cloning of a genomic fragment, designated S31, that has an open reading frame of 1095 nucleotides, encoding a protein of 365 amino acids. Amino acid similarity analysis suggested that the S31 protein could be a guanine nucleotide-binding protein-coupled receptor pertaining to the serotonin receptor subfamily. Expression of the S31 open reading frame in murine L cells confirmed this, because it led to the appearance of serotonin-mediated inhibition of adenylyl cyclase activity, which was absent in the recipient L cells. We now report some aspects of the pharmacological profile of this receptor. We found that the relative potencies with which 5-hydroxytryptamine, 5-Carboxamidotryptamine, methysergide, ergotamine, 8-hydroxydipropylaminotetralin, and trifluoromethylphenylpiperazine promote inhibition of adenylyl cyclase are as follows: 5-hydroxytryptamine >> methysergide >> ergotamine >> trifluoromethylphenylpiperazine > or = 8-hydroxydipropylaminotetralin > 5-carboxyamidotryptamine. This corresponds to the rank order of potencies assigned for these drugs for the 1E subtype of serotonin receptors discovered by Leonhardt and collaborators in human brain [J. Neurochem. 53:465-471 (1989)].

  • Sumatriptan contracts large coronary arteries of beagle dogs through 5-HT1-like receptors.
    Naunyn-Schmiedeberg's archives of pharmacology, 1992
    Co-Authors: Andrew A. Parsons, Cathy Stutchbury, Pravin Raval, Alberto J. Kaumann
    Abstract:

    The effects of 5-hydroxytryptamine (5-HT), 5-Carboxamidotryptamine (5-CT), methysergide and sumatriptan were studied on endothelium-denuded rings of beagle dog large coronary arteries. Submicromolar concentrations of the compounds contracted the rings with the order of potency 5-CT > 5-HT >sumatriptan = methysergide. Concentrations greater than 2 μM of both 5-HT and 5-CT, and 60 μmol/l methysergide also caused concentration-dependent relaxation. Sumatriptan did not cause relaxation. Peak intrinsic activities relative to the plateau contraction to sumatriptan (1.00), were 5-CT 0.47, 5-HT 0.87 and methysergide 0.51. Ketanserin 1 μmol/l affected neither contractile responses nor relaxant responses to 5-CT, methysergide and sumatriptan and only caused marginal blockade of the contractile effects of 5-HT. Methiothepin 200 nM shifted the concentration-contractile response curves by around 2 log units, as expected from its affinity for 5-HT1-like receptors.

  • a 5 ht4 like receptor in human right atrium
    Naunyn-schmiedebergs Archives of Pharmacology, 1991
    Co-Authors: Alberto J. Kaumann, Louise Sanders, Anthony M Brown, Kenneth J Murray, Morris J Brown
    Abstract:

    The effects of 5-Carboxamidotryptamine (5-CT) and the gastrokinetic benzamides renzapride and cisapride on contractile force were investigated using isolated paced right atrial appendages from patients treated with β-adrenoceptor blocking agents who were undergoing open heart surgery. These effects were compared to those of 5-hydroxytryptamine (5-HT). The effects of the drugs on atrial cyclic AMP levels and cyclic AMP-dependent protein kinase ratios were also investigated.

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