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)

(+)-8,9-Dihydro-10-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl) methyl]pyrido-[1,2-a]indol-6(7H)-one hydrochloride (FK1052) is a newly designed and synthesized 5-hydroxytryptamine (5-HT)3 receptor antagonist with 5-HT4 receptor antagonistic activity. This compound, as well as ondansetron and granisetron, dose-dependently inhibited the von Bezold-Jarish reflex, a 5-HT3 receptor-mediated response, after intravenous (i.v.) and intraduodenal (i.d.) dosing to rats. The ID50 values showed FK1052 (0.28 microgram/kg, i.v., 5.23 micrograms/kg, i.d.) to be more potent than ondansetron (5.23 micrograms/kg, i.v., 170 micrograms/kg, i.d.) and granisetron (0.70 micrograms/kg, i.v., 66 micrograms/kg, i.d.). Furthermore, bioavailabilities of the test drugs by ID50 ratio (i.d./i.v.) showed that FK1052(17) was better absorbed than ondansetron(33) and granisetron(94) and possessed a similar duration of action to that of ondansetron and granisetron. We also examined the effects on 2-methyl-5-HT-, 5-HT- and 5-methoxytryptamine-induced contractions of guinea pig isolated ileum. FK1052, ondansetron and granisetron concentration-dependently inhibited 2-methyl-5-HT, a 5-HT3 agonist-induced contraction. The pA2 values for the 5-HT3 receptor indicated that FK1052 (8.36) was 40 times and three times more potent than ondansetron (6.79) and granisetron (7.86), respectively. FK1052, unlike ondansetron and granisetron, inhibited the 5-HT4-mediated component of concentration-response curve to 5-HT. Furthermore, FK1052 suppressed 5-methoxytryptamine, a 5-HT4 agonist-induced contraction in a concentration-dependent but insurmountable manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological characterization of FK1052, a dihydropyridoindole derivative, as a new serotonin 3 and 4 dual receptor antagonist. 849 21

In species which vomit, elevated intestinal serotonin (5-hydroxytryptamine, 5-HT) may stimulate abdominal vagal afferent fibers, which in turn evoke the vomiting reflex. The release of 5-HT from intestinal enterochromaffin (EC) cells is regulated by polymodal mechanisms. The object of this study was to evaluate the involvement of 5-HT autoreceptors in the regulation of 5-HT release from the small intestine. Functional studies were carried out using 5-HT3 receptor agonist and antagonists, and 5-HT4 receptor agonist. Ferret and rat ileal tissue were isolated and 5-HT released into the bathing solution was determined using HPLC with an electrochemical detector (ECD). We previously reported that cisplatin produced a significant increase in cumulative 5-HT release and that ondansetron, a selective 5-HT3 receptor antagonist, did not alter the 5-HT release from the ferret ileum. In this study, a selective 5-HT3 agonist, 2-methyl-5-HT, induced a dose-dependent increase of 5-HT from the rat ileum. This release of 5-HT was significantly reduced by granisetron, a selective 5-HT3 receptor antagonist. Furthermore, a selective 5-HT4 receptor agonist, 5-methoxytryptamine induced a concentration-dependent increase of 5-HT in the rat ileum. These results suggest that both 5-HT3 and 5-HT4 receptors may be involved in intestinal 5-HT release.
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PMID:Chemical modulation of 5-HT3 and 5-HT4 receptors affects the release of 5-hydroxytryptamine from the ferret and rat intestine. 855 68

In the latter part of the 20th century, significant advances have been made in the understanding of the emetic reflex. As a result, there have been major improvements in the treatment of vomiting, particularly that associated with chemo- and radiotherapeutic treatments for neoplastic disease. The 5-HT3 receptor antagonists (ondansetron and granisetron) have been demonstrated to be of benefit in treating the profound emesis observed during cancer treatment. This observation, together with results from pharmacologic and physiologic investigations in both animals and humans, have identified 5-hydroxy-tryptamine (5-HT or serotonin) to be of fundamental importance in the pathogenesis of emesis. 5-HT appears to be released by radiation and chemotherapeutic agents from enterochromaffin cells within the wall of the intestine, and possibly from neurons within the brainstem. Stimulation of 5-HT3 receptors, located centrally in the dorsal medulla of the brainstem and peripherally on vagal afferent terminals in the gastrointestinal tract, appears to play a pivotal role in eliciting emesis. The interaction of 5-HT with non-5-HT3 receptors, particularly 5-HT1A and 5-HT4 receptors, may be important in the emetic reflex. The development of agents that interact with these receptors may offer alternative approaches to the treatment of nausea and vomiting.
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PMID:Serotonergic mediation of vomiting. 870 63

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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PMID:Investigation into the 5-hydroxytryptamine-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon. 873 67

The role of 5-hydroxytryptamine (5-HT), its enteric locus of action, and receptor subtypes involved in the regulation of jejunal contractions were investigated by close intra-arterial infusions in conscious dogs. Close intra-arterial infusions of 5-HT in short segments of the jejunum stimulated phasic contractions that were blocked completely by atropine, partially by tetrodotoxin, and not affected by hexamethonium. This response was also blocked significantly by 5-HT2A and 5-HT2C receptor antagonists but was not affected by 5-HT1A/5-HT1B, 5-HT3, and 5-HT4 receptor antagonists. Spontaneous phase III contractions were inhibited significantly by 5-HT2A and 5-HT2C receptor antagonists, not affected by 5-HT1A/5-HT1B and 5-HT3 receptor antagonists, and enhanced by 5-HT4 receptor antagonists. Repeated close intra-arterial infusions of 5-HT over several days stimulated giant migrating contractions. We conclude that in the conscious state, 5-HT acts on 5-HT2A and 5-HT2C receptors located on postsynaptic cholinergic neurons in the canine jejunum to stimulate phasic contractions and phase III activity. The 5-HT4 receptors in the canine small intestine may be localized on nonadrenergic, noncholinergic inhibitory neurons; these receptors suppress the amplitude and duration of phase III activity.
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PMID:5-HT-induced jejunal motor activity: enteric locus of action and receptor subtypes. 876 7

We examined the role of 5-hydroxytryptamine (5-HT) in cholera toxin (CT)-induced mucin secretion in the proximal and distal regions of the rat small intestine. Neither the 5-HT2 receptor antagonist ketanserin nor the cyclooxygenase inhibitor indomethacin was capable of inhibiting choleraic mucin secretion. However, in the presence of the mixed 5-HT3/4 receptor antagonist tropisetron at doses that block both receptor subtypes, the secretory response was reduced to baseline levels in the proximal and distal small intestine. The selective 5-HT3 receptor antagonist ondansetron had no significant effect. These findings suggest that choleraic mucin secretion is mediated primarily through the activation of a 5-HT4-like receptor. Mucin secretion in response to the exogenous application of 5-HT occurs via two pathways: one is mediated by a 5-HT4-like receptor and is capsaicin sensitive but tetrodotoxin (TTX) insensitive, and one lacks the capsaicin-sensitive 5-HT4-mediated response but is TTX sensitive. Both converge on a common pathway that is cholinergic. No significant differences were observed between proximal and distal intestinal segments.
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PMID:Role of 5-HT in cholera toxin-induced mucin secretion in the rat small intestine. 876 8

Serotoninergic neurones originating in the dorsal and median raphe nuclei project to mesolimbic structures, including the nucleus accumbens (NAcb) and the ventral tegmental area (VTA), where they may have an important regulatory role. Some evidence from dopamine release, behavioural and binding studies directly implicates involvement of 5-HT3 and 5-HT4 receptors in the NAcb. Other in vivo dopamine release and behavioural experiments in rats have provided evidence for 5-HT3 receptor-mediated enhancement of mesolimbic dopaminergic activity, although the location of the 5-HT3 receptors involved is unknown because the selective 5-HT3 receptor agents used were administered systemically or intracerebroventricularly. This raises the possibility of a VTA site of action; as yet, however, relatively little is specifically known about 5-HT receptors and function in the VTA. Mesolimbic dopamine release in rats, measured in-vivo with microdialysis probes in the NAcb, can be inhibited by tropisetron administered directly into the VTA. In our laboratory, behavioural studies in rats have shown that a sustained hyperlocomotion is produced by 2-methyl-5-HT administered into the VTA via stereotactically implanted guide cannulae. Mesolimbic dopaminergic activation is involved, because pretreatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine abolishes 2-methyl-5-HT-induced hyperlocomotion. The 2-methyl-5-HT hyperlocomotor response is blocked by prior intra-VTA injection of ondansetron but is not affected by methiothepin, and intra-VTA 5-carboxamidotryptamine, alpha-methyl-5-HT or renzapride were without effect, thus a 5-HT3 receptor in the VTA mediates the 2-methyl-5-HT response. These in vivo dopamine release and behavioural studies therefore confirm that 5-HT3 receptors in the VTA can mediate increased locomotor activity, by modulating the firing of mesolimbic dopaminergic cell bodies.
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PMID:Ventral tegmental area 5-HT receptors: mesolimbic dopamine release and behavioural studies. 878 68

In this brief review, we present the evidence for the regulation of the mesolimbic dopamine system by 5-HT3 and 5-HT4 receptors. A range of studies show good evidence that 5-HT3 receptor antagonists reduce raised mesolimbic dopamine activity by blocking 5-HT3 receptors in terminal parts of the mesolimbic dopamine system. Few studies have been conducted on the effects of 5-HT4 receptors on dopamine systems. However, it is clear that 5-HT4 receptors are present in relatively high density in areas of the brain that contain dopamine and preliminary studies show that 5-HT4 receptors may regulate the release of this transmitter.
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PMID:5-HT3 and 5-HT4 receptors in terminal regions of the mesolimbic system. 878 70

Enteric nerves express multiple receptors for 5-hydroxytryptamine (5-HT). Three excitatory and 1 inhibitory receptor for 5-HT can be identified using electrophysiological methods. The excitatory receptors are the 5-HT1P, 5-HT3 and 5-HT4 subtypes. The 5-HT1P mediates slow depolarizations (> 10 s duration) of many enteric nerves and 5-HT1P receptors mediate some slow excitatory synaptic potentials. The 5-HT3 receptor is a ligand-gated cation channel that mediates fast depolarizations (< 2 s). The 5-HT4 receptor mediates presynaptic facilitation of fast excitatory neurotransmission. The inhibitory receptor is the 5-HT1A receptor. 5-HT1A receptors mediate hyperpolarizations in AH neurons and presynaptic inhibition of fast and slow excitatory neurotransmission.
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PMID:Electrophysiological studies of 5-hydroxytryptamine receptors on enteric neurons. 878 2

The pathways and possible transmitters involved in the contractile response to selective 5-HT3 and 5-HT4 receptor stimulation in the guinea-pig proximal colon were studied. In the presence of methysergide, 5-HT induced contractions, yielding a biphasic concentration-response curve that was changed into a monophasic curve in the presence of the 5-HT3 receptor antagonist, granisetron (1 microM) (low-affinity phase blocked), or the 5-HT4 receptor antagonist, SB 204070 ((1-butyl-4-piperidinyl methyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate) (10 nM) (high-affinity phase blocked) combination of the two antagonists abolished the contraction to 5-HT. The effectiveness and selectivity of both antagonists was confirmed by testing them against contractions in response to the 5-HT3 receptor-selective agonist, 2-methyl-5-HT, and the 5-HT4 receptor-selective agonist, 5-methoxytryptamine. Hexamethonium (100 microM) did not affect the 5-HT3 receptor-mediated contractions, whereas tetrodotoxin (0.3 microM) caused only slight inhibition. Both in the absence and presence of tetrodotoxin, atropine (0.3 microM) inhibited the 5-HT3 receptor-mediated contractions. Hence, the contractions to 5-HT are partly mediated by 5-HT3 receptors that are localized on the nerve endings of the motor neurons. Hexamethonium halved the 5-HT4 receptor-mediated contractions, whereas tetrodotoxin abolished them. The 5-HT4 receptor-mediated contractions were inhibited by atropine (0.3 microM). Thus, the 5-HT4 receptors seem to be localized in the soma of the motor neurons; they also occur on interneurons. The remaining contractions induced by 5-HT3 and 5-HT4 receptor stimulation in the presence of atropine were almost completely inhibited by the tachykinin NK1 receptor antagonist, CP 96345 ((2S,3S)-cis-2-(diphenyl methyl)-N-[(2-methoxy phenyl)-methyl]-1-azabicyclo-[2.2.2]-octan-3-amine) (0.1 microM). CP 96345 also abolished or strongly inhibited contractions in response to substance P (10 nM) and to neurokinin A (30 nM), but neither granisetron nor SB 204070 affected them. Hence, stimulation of either 5-HT3 or 5-HT4 receptors induced contractions that are partially mediated by acetylcholine, and partially by a tachykinin NK1 receptor-stimulating neurotransmitter, probably substance P and/or neurokinin A.
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PMID:5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon. 884 Jan 29


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