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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.
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PMID:Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285. 132 Feb 4

The study concerned the effects of 5-hydroxytryptamine (5-HT) on intragastric pressure in bilaterally vagotomized spinal rats. Intravenous (i.v.) bolus injections of 5-HT (2.5, 5.0 and 10 micrograms/kg) produced dose-dependent increases in intragastric pressure; these effects were not modified by atropine (up to 0.2 mg/kg) or mepyramine (1 mg/kg), but were blocked by the mixed 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.1, 0.3 and 0.5 mg/kg i.v.) and methysergide (0.5, 1 and 2.5 mg/kg i.v.). However, metergoline (0.5, 1 and 2 mg/kg i.v.) did not markedly modify this effect of 5-HT; only the response induced by 5 micrograms/kg 5-HT was significantly antagonized by the highest dose of metergoline. In contrast, neither the 5-HT2 receptor antagonist, ketanserin (0.5, 1 and 1.5 mg/kg i.v.), nor the 5-HT3 receptor antagonist, ICS 205-930 (0.5, 1 and 3 mg/kg i.v.), influenced the 5-HT-induced increase in intragastric pressure. In addition, 5-carboxamidotryptamine (25, 50 and 100 micrograms/kg i.v.) and RU 24969 (50, 100 and 200 micrograms/kg i.v.) mimicked the aforementioned effects of 5-HT but were weaker than 5-HT. These data suggest that the 5-HT-induced increase in intragastric pressure in the spinal and bilaterally vagotomized rat is mediated by an atypical 5-HT1-like receptor, which, based on the low agonist potency of 5-carboxamidotryptamine and RU 24969 and the resistance to blockade by metergoline, does not seem to correspond to either the 5-HT1A, 5-HT1B, 5-HT1C or the 5-HT1D receptor subtypes.
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PMID:Role of 5-HT1-like receptors in the increase in intragastric pressure induced by 5-hydroxytryptamine in the rat. 152 63

Eleven subtypes of central 5-HT receptor have so far been postulated, four of which have been cloned (5-HT1A, 5-HT1C, 5-HT1D and 5-HT2) and a fifth (the 5-HT3 receptor) purified. The present review discusses the agonists and antagonists which act at these subtypes with respect to their degree of selectivity and in vivo potency. Selective agonists exist for the 5-HT1A, 5-HT1B and 5-HT3 receptors and selective antagonists for the 5-HT2 and 5-HT3 receptors.
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PMID:Centrally active 5-HT receptor agonists and antagonists. 155 8

The human saphenous vein preincubated with [3H]noradrenaline was used to determine the pharmacological properties of the release-inhibiting presynaptic serotonin (5-HT) receptor on the sympathetic nerves. The overflow of tritium evoked by transmural electrical stimulation (2 Hz) was concentration-dependently inhibited by drugs known to stimulate 5-HT receptors in the following rank order: oxymetazoline greater than or equal to 5-HT greater than 5-carboxamidotryptamine = 5-methoxytryptamine = sumatriptan greater than tryptamine greater than N,N(CH3)2-5-HT = yohimbine = 8-hydroxy-2-(di-n-propylamino)-tetraline. The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for 5-HT1B and 5-HT1D binding sites, but not with those for 5-HT1A or 5-HT1C binding sites. 5-Aminotryptamine, methysergide, ipsapirone, cyanopindolol, SDZ 21009 and metergoline dit not produce a significant inhibition. Metitepine and methysergide antagonized the inhibitory effect of 5-HT, whereas spiroxatrine, propranolol, ketanserin and ICS 205-930 did not. These data exclude the idea that the inhibitory presynaptic 5-HT receptor on the sympathetic nerves belongs to the 5-HT2 and 5-HT3 receptor class; the pattern of agonist potencies suggests that the receptor is very similar to the 5-HT1D receptor subtype.
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PMID:Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein via presynaptic 5-HT receptors similar to the 5-HT 1D subtype. 225 30

1. The aim of the present work was to characterize the presynaptic 5-HT receptors that mediate either the facilitation of the responses to nerve stimulation in the nictitating membrane of the cat or the inhibition of the responses to nerve stimulation in the guinea-pig atria. 2. In the nictitating membrane of the cat, the shift to the left in the frequency-response curves produced by 5-HT (0.1 microM) was prevented by the 5-HT3 receptor antagonists, metoclopramide (1 microM) and MDL 72222 (0.01 microM). 3. The facilitatory effect of 5-HT is also prevented by the 5-HT2 receptor antagonist, 0.01 microM ketanserin. Nevertheless, this drug reduced by itself the responses to both nerve stimulation and exogenous NA in the nictitating membrane. 4. In the guinea-pig isolated atria, the inhibitory effect of 5-HT on the chronotropic responses to cardioaccelerans nerve stimulation was mimicked by the mixed 5-HT1A + 5-HT1B + 5-HT1D receptor agonist 5-carboxamidotryptamine (5-CT 0.1 and 1 microM). The 5-HT1A receptor agonist 8-OH-DPAT (0.1 and 1 microM) did not modify the responses of the atria to the nerve stimulation. 5. The 5-HT2 receptor antagonists, ketanserin (0.01 and 0.1 microM) and cyproheptadine (1 microM), did not prevent the inhibitory effect of 5-HT in the guinea-pig atria. 6. The present results suggest that the facilitatory effects of 5-HT in the nictitating membrane of the cat are linked to the activation of 5-HT3 receptors whereas the inhibitory effects observed in the guinea-pig atria are mediated by 5-HT1-like receptors.
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PMID:Different receptor subtypes mediate the dual presynaptic effects of 5-hydroxytryptamine on peripheral sympathetic neurones. 252 97

3H-5-Hydroxytryptamine (5-HT) binding sites were analyzed in bovine brain membranes. The addition of either the 5-HT1A-selective drug 8-OH-DPAT (100 nM) or the 5-HT1C-selective drug mesulergine (100 nM) to the assay resulted in a 5-10% decrease in specific 3H-5-HT binding. Scatchard analysis revealed that the simultaneous addition of both drugs decreased the Bmax of 3H-5-HT binding by 10-15% without affecting the KD value (1.8 +/- 0.3 nM). Competition studies using a series of pharmacologic agents revealed that the sites labeled by 3H-5-HT in bovine caudate in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine appear to be homogeneous. 5-HT1A selective agents such as 8-OH-DPAT, ipsapirone, and buspirone display micromolar affinities for these sites. RU 24969 and (-)pindolol are approximately 2 orders of magnitude less potent at these sites than at 5-HT1B sites which have been identified in rat brain. Agents displaying nanomolar potencies for 5-HT1C sites such as mianserin and mesulergine are 2-3 orders of magnitude less potent at the 3H-5-HT binding sites in bovine caudate. In addition, both 5-HT2- and 5-HT3-selective agents are essentially inactive at these binding sites. These 3H-5-HT sites display nanomolar affinity for 5-carboxyamidotryptamine, 5-methoxytryptamine, metergoline, and 5-HT. Apparent Ki values of 10-100 nM are obtained for d-LSD, RU 24969, methiothepin, tryptamine, methysergide, and yohimbine, whereas I-LSD and corynanthine are significantly less potent. In addition, these 3H-5-HT labeled sites are regulated by guanine nucleotides and calcium. Regional studies indicate that this class of sites is most dense in the basal ganglia but exists in all regions of bovine brain. These data therefore demonstrate the presence of a homogeneous class of 5-HT1 binding sites in bovine caudate that is pharmacologically distinct from previously defined 5-HT1A, 5-HT1B, 5-HT1C, 5-HT2, and 5-HT3 receptor subtypes. We therefore suggest that this class of sites be designated the 5-HT1D subtype of binding sites labeled by 3H-5-HT.
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PMID:Characterization of a novel 3H-5-hydroxytryptamine binding site subtype in bovine brain membranes. 295 4

5-HT-induced acute gastric mucosal injury was assessed in rats by using 5HT1, 5HT2, 5HT3, 5HT4 or muscarinic receptor related drugs. Rats were treated with antagonists i.p. and 30 minutes later either vehicle, 5-HT (20 mg/kg) or other agonists were administered s.c. The stomachs were removed 4 hours after the last injection and mucosal integrity was assessed by light microscopy using a histological ulcer index (HUI). The HUI was found to be significantly increased following 5-HT administration (1.57 +/- 0.3) when compared with controls (0.14 +/- 0.1). 5HT1 agonist 5-carboxamidotryptamine (20 mg/kg) produced acute gastric erosion and increased the HUI (P < 0.05). The HUI in the animals receiving 5-HT1D agonist sumatriptan (7 mg/kg) was found to be 1.62 +/- 0.24. 5HT2 antagonist ketanserine (2.5-15 mg/kg), 5HT3 antagonist ondansetron (1-5 mg/kg), 5HT4 antagonist DAU 6285 (1-10 mg/kg) and atropine (1.5-30 mg/kg) exerted no effect whereas 5HT1/2 antagonist metitepine (0.05-0.5 mg/kg) caused a dose dependent inhibition of the effect of 5-HT. The results from this study demonstrate that 5-HT causes acute gastric mucosal injury and this injury is probably due to the activation of the 5-HT1D receptors.
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PMID:Serotonin causes acute gastric mucosal injury in rats, probably via 5HT1D receptors. 754 36

The purpose of this review is to describe the consequences of antidepressant treatment on the behaviour of rodents after activation of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes. In a summary table, the involvement of 5-HT receptors in inducing behavioural changes are described. It is emphasized that these effects are not always only exclusively linked to serotonergic functions nor that they are only initiated by central 5-HT receptors. Hereafter, the complex mutual inhibitory effects of 5-HT receptor subtype-mediated processes are discussed by interpreting effects of antagonists and describing the different effects of low and high doses of mixed 5-HT1C/5-HT2 receptor agonists. Mutual influences are seen particularly with 5-HT1A, 5-HT1C and 5-HT2, but not with 5-HT1B, 5-HT1D or 5-HT3 receptor-mediated effects. It is shown that the behavioural consequences of 5-HT1A, 5-HT1C and 5-HT2 receptor stimulation may be changed by brain lesions or chronic treatment with drugs. Among these drugs are the antidepressants. Finally, 5-HT receptor function in depressed patients is discussed, and the hypothesis is proposed that an important function of antidepressants is to restore a disturbed balance between 5-HT1A, 5-HT1C and 5-HT2 receptors in depressed patients.
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PMID:Interactions between 5-hydroxytryptamine receptor subtypes: is a disturbed receptor balance contributing to the symptomatology of depression in humans? 763 Sep 28

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.
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PMID:[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. 780 Oct 37

1. The aims of the present study were to determine whether long-term 5-hydroxytryptamine (5-HT) reuptake blockade and inhibition of type-A monoamine oxidase (MAO-A) lead to an enhancement of the electrically evoked release of tritum from guinea-pig brain slices preloaded with [3H]-5-HT, and to assess the sensitivity of the terminal 5-HT1D autoreceptor, the alpha 2-adrenoceptor also located on 5-HT terminals, and the 5-HT3 receptor that modulates 5-HT release following these two types of antidepressant treatments. 2. The electrically evoked release of tritium was significantly enhanced following a 21-day treatment with the 5-HT reuptake blocker, paroxetine and the reversible MAO-A inhibitor, befloxatone, in preloaded slices of the hypothalamus, hippocampus and frontal cortex 48 h after removal of the osmotic minipumps used to deliver the drugs. 3. The inhibitory effect of the terminal 5-HT autoreceptor agonist, 5-methoxytryptamine, on the evoked release of tritium was attenuated in slices of the hypothalamus, hippocampus, but not frontal cortex, following the paroxetine treatment. In the befloxatone group, the effectiveness of 5-methoxytryptamine was unaltered in the same brain structures. 4. The sensitivity of the alpha 2-adrenoceptor on 5-HT terminals, assessed using UK 14.304, was attenuated in hypothalamus, hippocampus, but not frontal cortex slices prepared from befloxatone-treated guinea-pigs and preloaded with [3H]-5-HT. The paroxetine treatment did not alter the sensitivity of this alpha 2-adrenoceptor in the hypothalamus. 5. The sensitivity of the alpha 2-adrenoceptor on noradrenaline terminals, also assessed using UK 14.304, was not altered in hippocampus and hypothalamus slices preloaded with [3H]-noradrenaline following the long-term befloxatone treatment. 6. In frontal cortex slices, [3H]-5-HT uptake was no longer significantly attenuated after a 21-day treatment with paroxetine, whereas it was still markedly inhibited in hypothalamus slices. The enhancing effect of paroxetine on the evoked release of [3H]-5-HT in the superfusion medium was no longer evident in frontal cortex slices of the paroxetine group. These data indicate that long-term 5-HT reuptake blockade desensitized the 5-HT transporter in the frontal cortex. 7. The capacity of the 5-HT3 receptor agonist, 2 methyl-5-HT, to enhance the electrically evoked release of tritium was not altered in hypothalamus, hippocampus, and frontal cortex slices prepared from befloxatone-treated guinea-pigs, but was significantly attenuated in the paroxetine group also treated for 21 days. Following a 2-day paroxetine treatment, the enhancing effect of 2-methyl-5-HT on tritium release was unaltered in frontal cortex slices.
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PMID:Modulation of 5-HT release in the guinea-pig brain following long-term administration of antidepressant drugs. 783


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