Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute levels of distension were applied by balloon to the colo-rectal region in conscious rats and visceromotor responses observed as abdominal muscle contraction; the threshold was typically between 10-40 mmHg. In saline-pretreated rats, the selective 5-HT3 (granisetron) and 5-HT4 (SB-207266) receptor antagonists had no effects on the visceromotor thresholds. 5-Hydroxytryptophan 10 mg/kg, subcutaneously (s.c.) decreased the distension threshold, indicating mechanical allodynia. This increased sensitivity was dose-dependently inhibited by granisetron but was unaffected by SB-207266 100 microg/kg, s.c., a dose which maximally and selectively antagonizes at 5-HT4 receptors. However, this dose of SB-207266 potentiated the inhibitory activity of submaximally-effective doses of granisetron, reducing the ED50 from 0.83 to 0.02 microg/kg, s.c., but without changing the maximum response or the bell-shaped nature of the dose-response curve for granisetron. These data suggest that 5-HT4 receptor activation enhances the ability of 5-HT3 receptor activation to induce intestinal allodynia.
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PMID:5-HT4 receptor antagonism potentiates inhibition of intestinal allodynia by 5-HT3 receptor antagonism in conscious rats. 1047 Dec 14

The involvement of 5-HT2 receptor subtypes in mediating a contraction response in the isolated intestine of Suncus murinus was investigated using DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane, a 5-HT2 receptor agonist) which produced a bell-shaped concentration response curve that was significantly (p < 0.05) reduced by methysergide (a 5-HT1/2 receptor antagonist, 1 microM) but not ketanserin (a 5-HT2A receptor antagonist, 1 microM), yohimbine (a 5-HT2B receptor antagonist, 1 microM) or a combination of ondansetron (a 5-HT3 receptor antagonist, 1 microM) plus SB204070 (8-amino-7-chloro(N-butyl-4-piperidyl) methylbenzo-1,4-dioxan-5-carboxylate hydrochloride, a 5-HT4 receptor antagonist, 1 nM). The contraction response to the lower concentrations of DOI (10 nM-0.3 microM) was reduced in the presence of SB206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole, a 5-HT2B/2C receptor antagonist, 1 microM), whilst conversely, the reducing response to the higher concentrations of DOI (1-30 microM) was prevented. A repeated challenge with 3 microM DOI produced a smaller response (desensitisation) and also reduced the response to 5-HT (5-hydroxytryptamine, 0.3 microM) that was inhibited by SB206553 (1 microM). Data indicate that 5-HT2C receptors are likely candidates to mediate the contractile response to DOI and demonstrate desensitisation to repeated challenges.
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PMID:Characterisation of 5-HT2 receptor subtypes in the Suncus murinus intestine. 1055 84

The involvement of serotonin (5-HT) receptor subtypes in motor activity of the ex vivo vascularly perfused rat duodenum was investigated. Clusters of phasic contractions (CPCs), migrating in an oral to anal direction, were obtained without any stimulation. Drug effects were evaluated by changes in different components of the pressure waves, such as motor index (MI), frequency, amplitude and duration of the CPC. The effect of 5-HT depletion on motor activity was examined in animals treated with p-chlorophenylalanine (PCPA). The MI, frequency and duration of CPC were decreased by PCPA, but the amplitude was not affected, suggesting that endogenous 5-HT may play an important role in regulation of the motor activity of the rat intestine. The importance of the 5-HT receptor subtypes in the regulation of motor activity was examined. Neither the nonselective 5-HT1 and 5-HT2 receptor antagonist, methysergide, nor the 5-HT2 receptor antagonist, ketanserin, affected motor activity. However, the 5-HT3 receptor antagonists, granisetron and azasetron, decreased percentage MI, frequency, percentage amplitude and percentage duration of CPC. The 5-HT4 receptor antagonist, SB204070, exerted both excitatory and inhibitory actions, with a higher dose (10 nM) stimulating percentage MI, frequency, percentage amplitude and percentage duration, and a lower dose (0.1 nM or 1 nM) decreasing percentage MI and percentage duration of CPC. These results suggest that endogenous 5-HT regulates the motor activity of the rat duodenum through 5-HT3 and 5-HT4 receptors, with the former mediating the stimulatory influence and the latter mediating both stimulatory and inhibitory influences.
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PMID:Involvement of 5-HT3 and 5-HT4 receptors in the motor activity of isolated vascularly perfused rat duodenum. 1058 53

New benzimidazole-4-carboxamides 1-16 and -carboxylates 17-26 were synthesized and evaluated for binding affinity at serotonergic 5-HT4 and 5-HT3 receptors in the CNS. Most of the synthesized compounds exhibited moderate-to-very high affinity (in many cases subnanomolar) for the 5-HT4 binding site and no significant affinity for the 5-HT3 receptor. SAR observations and structural analyses (molecular modeling, INSIGHT II) indicated that the presence of a voluminous substituent in the basic nitrogen atom of the amino moiety and a distance of ca. 8.0 A from this nitrogen to the aromatic ring are of great importance for high affinity and selectivity for 5-HT4 receptors. These results confirm our recently proposed model for recognition by the 5-HT4 binding site. Amides 12-15 and esters 24 and 25 bound at central 5-HT4 sites with very high affinity (Ki = 0.11-2.9 nM) and excellent selectivity over serotonin 5-HT3, 5-HT2A, and 5-HT1A receptors (Ki > 1000-10,000 nM). Analogues 12 (Ki(5-HT4) = 0.32 nM), 13 (Ki(5-HT4) = 0.11 nM), 14 (Ki(5-HT4) = 0.29 nM) and 15 (Ki(5-HT4) = 0.54 nM) were pharmacologically characterized as selective 5-HT4 antagonists in the isolated guinea pig ileum (pA2 = 7.6, 7.9, 8.2 and 7.9, respectively), with a potency comparable to the 5-HT4 receptor antagonist RS 39604 (pA2 = 8.2). The benzimidazole-4-carboxylic acid derivatives described in this paper represent a novel class of potent and selective 5-HT4 receptor antagonists. In particular, compounds 12-15 could be interesting pharmacological tools for the understanding of the role of 5-HT4 receptors.
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PMID:Benzimidazole derivatives. Part 1: Synthesis and structure-activity relationships of new benzimidazole-4-carboxamides and carboxylates as potent and selective 5-HT4 receptor antagonists. 1063 37

The functions of the 5-hydroxytryptamine3 (5-HT3) and 5-hydroxytryptamine4 (5-HT4) receptors in gastrointestinal tract are complex depending on the species and anatomical regions, and the localization of these receptors in the human rectum was unclear. We examined the localization of the 5-HT3 and 5-HT4 receptors in human rectum by in vitro receptor autoradiography using [125I](S)iodozacopride and [125I] SB207710 as a ligand, respectively. Specific [125I](S)iodozacopride binding sites were clearly evident in the myenteric plexus, whereas, low levels of [125I]SB207710 binding sites were distributed over the muscle but not to the myenteric plexus. The 5-HT3 receptor located on the myenteric plexus and the 5-HT4 receptor on the smooth muscle may participate in contractility and relaxation of human rectum, respectively.
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PMID:Differential localization of 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in the human rectum. 1065 21

The role of 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptors in the regulation of gut motility in the ferret was investigated. The selective 5-HT3 receptor antagonist ramosetron (1 - 10 microg/kg s.c.) prolonged the interval of gastric antral migrating motor complex, but had only slight effect on small intestinal and colonic motility in unfed animals. The selective 5-HT4 receptor antagonist SB 204070 did not affect motility throughout gut in unfed animals. Neither ramosetron nor SB 204070 affected the motility throughout gut in fed animals. In conclusion, neither 5-HT3 nor 5-HT4 receptors tonically regulate ferret gut motility except that 5-HT3 receptors have a key role in the occurrence of migrating motor complex specifically in the stomach. The role of 5-HT3 and 5-HT4 receptor system in the regulation of gut motility in ferrets is similar to that in other mammalian species studied, including humans. This similarity suggests that the ferret is a suitable model animal to study gut motor functions in humans.
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PMID:The role of 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in the regulation of gut motility in the ferret. 1086 3

The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo. The underlying mechanism was studied by recording the accumulation of 5-hydroxytryptophan (5-HTP) in hypothalamus and hippocampus after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Depletion of 5-HT with reserpine markedly reduced the citalopram-induced decrease of 5-HTP but not that evoked by the 5-HT1A receptor agonist 8-OH-DPAT, which indicates that the presence of endogenous 5-HT is necessary for full effect of citalopram. In contrast to the almost complete antagonism of the decrease in 5-HT synthesis induced by 8-OH-DPAT, the 5-HT1A receptor antagonist WAY-100,635 only slightly affected the citalopram-evoked decrease in 5-HT synthesis. Likewise, the 5-HT1B receptor antagonists NAS-181 and GR127935 only slightly antagonised the citalopram effect although they strongly inhibited the decrease in 5-HT synthesis induced by the 5-HT1B receptor agonist anpirtoline. Combined treatment with 5-HT1A and 5-HT1B receptor antagonists did not produce any additive antagonistic effect on the citalopram-induced decrease in 5-HT synthesis. The 5-HT2A/2C receptor antagonist ketanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT4 receptor antagonist RS-39604 had no effect on the citalopram-induced decrease in 5-HT synthesis. The same was found for several other non-selective 5-HT receptor antagonists, e.g. cyproheptadine, dihydroergotamine, methiothepin, methysergide, metergoline and mianserin. It is concluded that the citalopram-induced decrease in 5-HT synthesis differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor agonists and citalopram also seems to require endogenous 5-HT for its full effect.
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PMID:Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram. 1121 75

Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity.
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PMID:Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. 1129 43

Irritable bowel syndrome (IBS) is a functional gut disorder the diagnosis of which is based on clinical symptoms as set forth by the Rome criteria. As the population ages, especially with the population of patients >75 years of age expanding greatly over the next 10 years, IBS is becoming one of the most common diseases of the elderly. Thus far, developing treatment strategies for patients with IBS has been difficult because of the lack of pharmacological targets and the wide range of symptomatology. Additionally, demonstration of a therapeutic benefit is difficult in the presence of a high placebo response observed regardless of the therapy employed. Fibre, antidiarrhoeals and antispasmodics all play some role in the symptomatic treatment of IBS. With the evolution of IBS as a disorder of visceral hypersensitivity, new drugs have been developed that target the enteric nervous system. Tricyclic antidepressants (TCAs) have been found to target the enteric neurons and play a role in pain modulation. Currently, the TCAs are recommended only for severe cases of IBS pain. The newest class of drugs to be approved for use in IBS are the serotonin (5-hydroxytryptamine; 5-HT) antagonists. Specifically, the 5-HT3 receptor antagonists have been shown to decrease symptoms in female patients with IBS. A related class of drugs, the 5-HT4 receptor agonists, is being developed for the treatment of constipation-predominant IBS. Further investigation into the role of spinal afferent neurons in visceral hypersensitivity is at the forefront of IBS research. Several experimental drug therapies for IBS are also discussed in this review including N-methyl-D-aspartate receptor antagonists, neurokinin-1 receptor antagonists, octreotide, clonidine and the selective M3 receptor antagonist, zamifenacin.
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PMID:Drug treatment options for irritable bowel syndrome: managing for success. 1130 87

This work reports the synthesis and the binding tests on the 5-HT3 and 5-HT4 receptors of new thienopyrimidopiperazine and piperazinylacylaminodimethylthiophene derivatives, in order to identify potent and selective ligands for each receptor. The 3-amino-2-(4-benzyl-1-piperazinyl)-5,6-dimethyl-thieno[2,3-d]pyrimidin-4(3H)-one derivative 28 showed the highest affinity and selectivity for the 5-HT3 over the 5-HT4 receptor (5-HT3 Ki=3.92 nM, 5-HT4 not active), whereas the 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butanoylamino]-4,5-dimethyl-3-thiophenecarboxylic acid ethyl ester (41) showed the highest affinity and selectivity for the 5-HT4 over the 5-HT3 receptor (5-HT4 Ki=81.3 nM, 5-HT3 not active). Conformational analyses were carried out on the compounds of the piperazinylacylaminodimethylthiophene series (39-42) taking compound 41 as the template.
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PMID:Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands. 1124 5


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