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

Specific binding for the serotonin 5-HT4 receptor (5-HT4R) radioligand [3H]GR 113808 was identified in pig caudate nucleus and characterized by serotonin subtype selective drugs. Binding was inhibited by serotonin and by synthetic indoles, benzamides and benzimidazolones known to characterize the 5-HT4R in functional tests. Rank order of potency of 5-HT4R antagonists was: GR 125487 (Ki, 0.19 nM) > GR 113808 >> SC 53606 > SDZ 205,557 > RS 235971/190 > DAU 6285 > tropisetron > DAU 6215. GR 125487 and GR 113808 were highly selective with respect to the 5-HT3 receptor (5-HT3R). Rank order of potency of 5-HT4R agonists was: SC 53116 (Ki, 21 nM) > BIMU 1 > cisapride > BIMU 8 > serotonin > renzapride > S-zacopride > metoclopramide > R-zacopride > 5-methoxytryptamine >> 5-carboxamidotryptamine. BIMU 8, renzapride, metoclopramide and the zacopride enantiomers gave shallow competition curves. The agonists were substantially less selective than the antagonists with respect to the 5-HT3R. With only two exceptions, SCH 23390 and metergoline, which bound with sub-microM affinity to the 5-HT4R, binding was not inhibited by compounds selective for other G-protein-coupled or channel-gated receptors. Highly significant correlations in affinities of compounds for 5-HT4R in caudata of pigs, guinea pigs and humans were found suggesting no difference among mammalian species.
 ...
PMID:Identification of serotonin 5-HT4 recognition sites in the porcine caudate nucleus by radioligand binding. 798 93

The pharmacological properties of the (R) and (S) enantiomers of RS 56532 have been studied in vitro and in vivo. In radioligand binding studies at 5-HT4 receptors in guinea-pig striatum, (S) RS 56532 exhibited a higher affinity than (R) RS 56532 (-log Ki = 7.6 and 6.5, respectively). (S) RS 56532 acted as a potent agonist at 5-HT4 receptors mediating relaxation of rat oesophageal muscularis mucosae (-log EC50 = 7.9) while (R) RS 56532 acted as a weaker agonist at this receptor (-log EC50 < 6.0). These data suggest that at 5-HT4 receptors, the enantiomeric selectivity of RS 56532 was (S) > (R). In binding studies at 5-HT3 receptors in rat cortex, (R) RS 56532, conversely, exhibited a higher affinity than (R) RS 56532 (-log Ki = 9.1 and 8.0, respectively). At 5-HT3 receptors in guinea-pig isolated ileum, (R) RS 56532 exhibited an affinity (-log KB) of 7.9, whereas (S) RS 56532 (1 nM-1 microM) was inactive. No agonism was observed at ileal 5-HT3 receptors with either enantiomers. These data suggest that at 5-HT3 receptors in rat and guinea-pig, both enantiomers acted as antagonists, with (R) > (S) RS 56532. At the non-5-HT3, high affinity '(R) zacopride' site, (R) RS 56532 exhibited a higher affinity than (S) RS 56532 (-log Ki = 6.1 and 4.9). This site was insensitive to potent 5-HT3 antagonists such as (R) YM 060 or ondansetron. However, it was recognized with relatively high affinity (-log Ki = 7.5) by the (R), but not (S) enantiomer, of RS 42358 (-log Ki = 4.7). Since (S) RS 42358 is a high affinity 5-HT3 receptor antagonist, these data further highlight the dissimilarity between the 5-HT3 receptor and the '(R) zacopride' site. The '(R) zacopride' site also appeared to be pharmacologically distinct from the 5-HT4 receptor, since 5-HT4 ligands such as renzapride, SDZ 205,557 or RS 23597-190 exhibited low affinities. The enantiomeric selectivity of (R) and (S) RS 56532 in vivo was consistent with findings in vitro. At 5-HT4 receptors mediating tachycardia in the pig, 5-HT induced a dose-dependent tachycardia (ED50 = 3 micrograms kg-1, i.v.; maximum response = 90-100 beats min-1). (S) RS 56532 increased heart rate by 88 min-1 with a potency of (ED50) of 3 micrograms kg-1, i.v.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:(R) and (S) RS 56532: mixed 5-HT3 and 5-HT4 receptor ligands with opposing enantiomeric selectivity. 798 91

An additional component of the depolarization induced by 5-hydroxytryptamine (5-HT) in the rat isolated vagus nerve has recently been attributed to activation of 5-HT4 receptors. To confirm and extend this finding, extracellular recordings of D.C. potentials were made using the 'grease-gap' technique during continuous superfusion of the isolated nerve. Beginning at 1 nM, 5-HT induced small depolarizations that displayed a slow onset. At concentrations > or = 1 microM, large depolarizations with rapid onset were elicited. In the presence of the 5-HT3 receptor antagonists, granisetron or ondansetron, 5-HT responses were diminished and exhibited an increased latency to peak. These small, slow depolarization were not reduced by 5-HT1 or 5-HT2 receptor antagonists, but were potently inhibited by the 5-HT4 receptor antagonist GR 113808 (pA2 = 9.3), and mimicked by 5-methoxytryptamine (pEC50 = 5.3). 5-HT4-mediated responses were larger at 37 degrees C than at 31 degrees C, but also showed marked diminution with repeated 5-HT applications at concentrations greater than 1 microM. Conversely, 5-HT3 receptor responses were potentiated at lower temperatures (< or = 31 degrees C). Consistent with the reported positive coupling of 5-HT4 receptors to adenylyl cyclase, forskolin and 8-Br-cAMP produced slowly developing depolarizations which were qualitatively similar to 5-HT4 receptor activation. Pre-depolarization of nerves with 10 microM forskolin or 300 microM 8-Br-cAMP diminished the effect of 5-HT4 receptors. This study has confirmed the presence of 5-HT4 receptors on the vagus nerve of the rat and defined some conditions that optimize their pharmacological isolation.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Characterization of 5-hydroxytryptamine-induced depolarizations in rat isolated vagus nerve. 798 37

1. The receptor subtypes through which 5-hydroxytryptamine (5-HT) increases electrolyte secretion across the mucosa of guinea-pig ileum were studied. 2. Flat sheep preparations of guinea-pig mucosa plus submucosa were placed in Ussing chambers and the short circuit current (ISC), an index of net electrogenic electrolyte transport across the mucosa, was measured under voltage clamp conditions. 3. Low concentrations of 5-HT (10-300 nM) evoked monophasic increases in ISC which were significantly reduced by hyoscine (100 nM), tetrodotoxin (TTX, 300 nM) and the 5-HT2 receptor antagonist, ketanserin (3-300 nM). 4. Higher concentrations of 5-HT (1-10 microM) produced biphasic responses which were reduced by hyoscine (100 nM), TTX (300 nM), ketanserin (3-300 nM) and also by the 5-HT3 receptor antagonists, granisetron (1 microM) and ICS 205-930 (100 nM). 5. 2-Methyl-5-HT (1-100 microM) and alpha-methyl-5-HT (30 nM-30 microM), agonists at 5-HT3 and 5-HT2 receptors respectively, also evoked ISC increases. These responses were reduced by hyoscine (100 nM) and abolished by TTX (300 nM) and the respective receptor antagonists, granisetron (1 microM) and ketanserin (30 nM). 6. The 5-HT4 receptor antagonist, SDZ 205-557 (300 nM) had no effect on the response to 5-HT. 7. The TTX-resistant response to 5-HT was not affected by 5-HT2,3 or 4 receptor antagonists. 8. These results indicate that 5-HT mediates secretion partly by an action on 5-HT3 receptors located on cholinergic and noncholinergic secretomotor neurones, partly by an action on higher affinity'5-HT2-like' receptors predominantly on noncholinergic neurones, and partly by a direct action on the epithelium.
 ...
PMID:Characterization of 5-hydroxytryptamine receptors mediating mucosal secretion in guinea-pig ileum. 803 11

We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action. BIMU 1 dose-dependently (0.01-0.3 mg/kg i.v.) increased the motility of a denervated pouch of canine stomach. This excitatory action was sensitive to muscarinic blockade. A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03-0.3 mg/kg i.v.) but not by the 5-HT3 receptor antagonist ondansetron (up to 1 mg/kg i.v.). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog. The emptying rate of a non-caloric liquid meal instilled through a gastric fistula was accelerated by both BIMU 1 (0.01-1 mg/kg i.v. and 0.1-3 mg/kg p.o.) and cisapride (0.03-1 mg/kg i.v. and 0.3-10 mg/kg p.o.). Ondansetron (1 mg/kg i.v.) did not show any effect. The activity of the 5-HT4 receptor antagonist DAU 6285 was evaluated in the gastric emptying model per se and in interaction experiments on the accelerating action of BIMU 1 (0.3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors. 805 5

The effects and sites of action of 5-HT3 and 5-HT4 receptor agonists and antagonists on the abomasal myoelectric activity were examined in conscious sheep, chronically fitted with intravenous (i.v.) and intracerebroventricular (ICV) cannulas and intraparietal electrodes on the gastric body and antrum. The 5-HT3 receptor agonist 2-methylserotonin, injected either i.v. (150 micrograms/kg) or ICV (5 micrograms/kg), induced an inhibition of the spiking activity in both the gastric body and antrum. This inhibition was abolished when the 5-HT3 antagonist granisetron was preinjected either i.v. (150 micrograms/kg) or ICV (15 micrograms/kg). The i.v. injection of 5-HT4 agonist 5-methoxytryptamine (200 micrograms/kg) initially provoked stimulation and thereafter inhibition of abomasal activity, while its ICV administration (10 micrograms/kg) resulted in only inhibition of the gastric body activity. BIMU 1, another 5-HT4 agonistic substance, injected i.v. (300-1000 micrograms/kg), mimicked only the stimulatory actions of 5-methoxytryptamine, while its ICV administration (10-50 micrograms/kg) had no effect on the abomasal activity. The i.v. (2000 micrograms/kg), but not the ICV (100 micrograms/kg), pre-injection of the 5-HT4 antagonist DAU 6285 blocked the stimulation of the abomasal spiking activity resulting from the i.v. injection of either 5-methoxytryptamine or BIMU 1. These results suggest that, in sheep, inhibitory 5-HT3 and excitatory 5-HT4 receptors, located at brain and peripheral levels respectively, participate in the control of the abomasal contractions.
 ...
PMID:Motor-modifying properties of 5-HT3 and 5-HT4 receptor agonists on ovine abomasum. 809 91

The anorectic responses to imbalanced amino acid diets (IMB) are ameliorated by pretreatment with large (mg/kg) doses of the serotonin antagonists, tropisetron [3-alpha-tropanyl-1H-indole-3-carboxylic acid ester, formerly known as ICS-205,930 (ICS)] and MDL 72,222 [1 alpha H,3 alpha,5 alpha-H-tropan-3-yl-3,5-dichlorobenzoate (MDL)], effects earlier attributed to the 5-hydroxytryptamine3 (5-HT3) receptor. Subsequent identification of the 5-HT4 receptor, and recognition that ICS and MDL also bind to 5-HT4 receptors, led us to question whether the results seen with these drugs were due to activity at the 5-HT3 or 5-HT4 receptor subtype. 1,2,3,9-Tetrahydro-9-methyl-3 [(2-methyl-1H-imidazol-1-yl) methyl] 4H-carbazol-4-one) [ondansetron (OND)], a reportedly 5-HT3-selective receptor antagonist, has been used to block 5-HT3 receptors in demonstrating the 5-HT4 receptor, and so seems securely selective for the 5-HT3 receptor type. Therefore, we tested the effects of OND on the rat's feeding responses to IMB. Pretreatment with 0.1 or 1 micrograms/kg OND fully restored intake of IMB to > 100% of control between 6 and 12 h after introduction of IMB. We conclude that the previous similar increases in IMB intake seen after ICS and MDL were due to their antagonist activity at the 5-HT3 receptor and that the 5-HT3 receptor may have an important role in mediating the rat's anorectic responses to IMB.
 ...
PMID:Anorectic response to amino acid imbalance: a selective serotonin3 effect? 811 29

The actions of 5-hydroxtryptamine (5-HT)1A and 5-HT4 receptor agonists on fast excitatory postsynaptic potentials (EPSPs) in myenteric neurons of guinea pig ileum were studied in vitro. Intracellular electrophysiological methods were used to record EPSPs. 5-HT (0.1 microM), 5-carboxamidotryptamine (0.001-0.1 microM), 8-hydroxydipropylaminotetralin (0.003-0.3 microM), and 5-methoxytryptamine (5-MeOT; 0.3 microM) inhibited EPSPs. Agonist inhibition of EPSPs was blocked by the 5-HT1A receptor antagonists, spiperone and NAN-190. In the presence of NAN-190 (0.3 microM), 5-HT (0.001-0.1 microM) increased EPSP amplitude. 5-MeOT (0.001-0.1 microM), renzapride (0.01-0.3 microM), cisapride (0.01-1 microM), and BIMU 8 (0.003-0.1 microM) increased EPSP amplitude but did not change the membrane potential of any neuron. EPSP potentiation induced by each agonist was blocked by the 5-HT3/5-HT4 receptor antagonist, tropisetron (1 microM), but not by the 5-HT3 receptor antagonist, ondansetron (1 microM). Potentiation of fast EPSPs by 5-HT (0.1 microM) desensitized, whereas renzapride (0.1 microM) responses did not. Desensitization induced by BIMU 8 was variable. These data indicate that enteric 5-HT1A and 5-HT4 receptors function to inhibit and facilitate transmitter release, respectively. 5-HT4-mediated facilitation of ganglionic neurotransmission could contribute to the prokinetic effects of cisapride and renzapride.
 ...
PMID:5-HT1A and 5-HT4 receptors mediate inhibition and facilitation of fast synaptic transmission in enteric neurons. 814 Dec 96

New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
 ...
PMID:Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties. 817 10

Dumuis and colleagues (1988) in their investigation of a 5-HT receptor positively linked to adenylate cyclase in the central nervous system, concluded that the receptor was not 5-HT1, 5-HT2 or 5-HT3-like and suggested that it belonged to a new class of 5-HT receptor called 5-HT4. A similar, if not identical receptor was located by Craig and Clark (1990) in the guinea pig ileum and a functional role for the peripheral 5-HT4 receptor has since been established in many species to mediate muscle contraction or relaxation within the gut and positive inotropic effects in the heart. In contrast, a functional role for central 5-HT4 receptors has remained obscure. Using measurements of rodent behaviour in the mouse light and dark test box and rat social interaction, anxiolytic agents such as diazepam and putative anxiolytic agents such as the 5-HT1A and 5-HT3 receptor ligands 8-OH-DPAT and low doses of tropisetron release behaviour suppressed by the aversive situation. 5-Hydroxytryptophan has the opposite effect exacerbating the behavioural response to the aversive situation. But an anxiolytic profile is revealed by co-treatment with ritanserin plus 5-hydroxytryptophan. The drug-induced anxiolytic profiles are inhibited by SDZ205-557 and a high dose of tropisetron. Both compounds are 5-HT3/5-HT4 receptor antagonists yet the selective 5-HT3 receptor antagonist ondansetron fails to inhibit the drug-induced anxiolytic profiles.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The pharmacology of the 5-HT4 receptor. 820 Dec 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>