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)

Recent evidence suggests that serotonin plays an important role in learning and memory processes in animals. The present study examined the effect of the 5-HT3 receptor antagonist, granisetron (BRL 43694), on acquisition, retention and retrieval of a passive avoidance response in mice. Granisetron (1 and 10 micrograms/kg) administered 30 min before presentation of footshock increased the step-down latency when tested 24 h after footshock. The acquisition process was not affected by a dose of 100 micrograms/kg. Granisetron (10 and 100 micrograms/kg) produced a significant increase in latency to step out of the safety zone, when administered immediately after or 23.5 h after footshock. However, at 1 microgram/kg, granisetron had no effect. These results confirm the important role played by 5-HT in the process of learning and memory, and also suggest that memory enhancement may be possible with non-cholinergic treatments.
 ...
PMID:Memory enhancing effects of granisetron (BRL 43694) in a passive avoidance task. 166 86

Studies have been carried out on 7 male adult rats to investigate how the action of the selective 5-HT3 receptor antagonist, granisetron, influences gastrointestinal transit under control conditions and when it is delayed by ileal infusion of lipid. Stomach to caecum transit time (SCTT) was measured using environmental hydrogen analysis. Subcutaneous administration of granisetron (BRL 43694, 40 micrograms kg-1) significantly delayed the passage of the head of the baked bean meal through the stomach and the small intestine under control conditions (P less than 0.05). The same compound, however, significantly reversed the delay in SCTT induced by ileal infusion of lipid (P less than 0.001). These apparently paradoxical results may be rationalized by postulating inhibition of receptors on afferent nerves initiating reflexes that both accelerate and delay transit.
 ...
PMID:The effect of a 5-HT3-antagonist on the ileal brake mechanism in the rat. 168 69

5-HT3 receptors may be present on primary afferent neurons containing substance P (SP), neurokinin A (NKA) or calcitonin gene-related peptide (CGRP). We investigated the release of SP-, NKA- and CGRP-immunoreactivities (IR) from rat spinal cord slices. Thirty mM potassium chloride caused an increased outflow of all three peptides, i.e. 140-190% of spontaneous release. This release was slightly enhanced in the presence of 3 x 10(-5) M 5-hydroxytryptamine (5-HT). In contrast, a significant inhibition of potassium-evoked, but not of basal NKA-IR and CGRP-IR release was observed when 10(-7) M BRL 43694 or ICS 205-930, two specific 5-HT3 receptor antagonists, were superfused together with 5-HT. In conclusion, 5-HT may facilitate the evoked release of peptides from central terminals of primary sensory neurons via 5-HT3 receptors.
 ...
PMID:5-HT3 receptor antagonists inhibit sensory neuropeptide release from the rat spinal cord. 171 37

The serotonin (5-hydroxytryptamine, 5-HT) antagonists, which bind at the type 3 receptor (5-HT3 receptor), have been evaluated in several preclinical models and found to be effective in alleviating cancer therapy-related emesis. The antiemetic efficacy of ondansetron (GRF-38032F, odanserin), granisetron (BRL-43694), tropisetron (ICS-205930), MDL-72222 and MDL-73147EF, batanopride (BMY-25801-01) and several others is at various stages of investigation. Ondansetron is currently marketed in several countries and the same will soon be true for granisetron. At this stage it is not yet possible to evaluate the comparative efficacy of each of these compounds, although recent preclinical data reveal some differences in the affinity of these compounds, for other receptors. Side effects related to these agents have been minor, consisting mainly of slight headaches; possible rises in liver enzymes related to some compounds need further evaluation. Future studies will need to determine the exact role of 5-HT3 antagonists, although their cost may confine their use to patients at high risk for side effects from metoclopramide.
 ...
PMID:5-HT3 receptor antagonists. An overview of their present status and future potential in cancer therapy-induced emesis. 172 61

Granisetron (BRL 43694) is a highly selective 5-HT3 receptor antagonist which possesses significant antiemetic activity, likely mediated through antagonism of 5-HT3 receptors on abdominal vagal afferents and possibly in or near the chemoreceptor trigger zone. Clinical trials in cancer patients demonstrate that, compared with placebo, granisetron significantly reduces the incidence of nausea and vomiting for 24 hours after administration of high-dose cisplatin. In large comparative trials, 70% of patients who received granisetron prior to cisplatin or other chemotherapy experienced complete inhibition of vomiting with little or no nausea for 24 hours after antineoplastic administration; these results were similar to those obtained with high-dose metoclopramide plus dexamethasone, and superior to a combination of chlorpromazine plus dexamethasone, or prochlorperazine plus dexamethasone, or methylprednisolone monotherapy. The most frequently reported adverse event associated with granisetron administration is headache which occurs in about 10 to 15% of patients while constipation, somnolence, diarrhoea and minor transient changes in blood pressure have been reported less frequently. Extrapyramidal effects, which can occur with high-dose metoclopramide and may be a limiting factor in its use, have not been noted with granisetron administration. Thus, granisetron is an effective, well tolerated and easily administered agent for the prophylaxis of nausea and vomiting induced by cancer chemotherapy which appears to be devoid of extrapyramidal side effects associated with metoclopramide. As a member of a new class of drugs, the selective 5-HT3 receptor antagonists, granisetron provides the medical oncologist with a new, potentially more acceptable antiemetic therapy.
 ...
PMID:Granisetron. A review of its pharmacological properties and therapeutic use as an antiemetic. 172 76

In the present experiments we have investigated the possible coupling of 5-hydroxytryptamine (HT)3 receptors to the metabolism of phosphatidylinositol (PI) in the rat fronto-cingulate and entorhinal cortices, two brain regions with relatively high density of this receptor subtype. 5-HT dose-dependently increases PI turnover (20-80% increase above basal stimulation), with an EC50 of 0.5 and 0.3 microM for fronto-cingulate and entorhinal cortices, respectively. This effect was blocked by the selective 5-HT3 antagonists, BRL 43694 (granisetron), GR 38032F (ondansetron) and ICS 205-930. The selective 5-HT3 receptor agonists, 2-methyl-serotonin (2-Me-5-HT) and phenylbiguanide (PBG), mimicked the action of 5-HT and dose-dependently produced a significant increase in PI turnover (46-76% of the 5-HT response). The stimulatory action of 2-Me-5-HT and phenylbiguanide was blocked completely by granisetron, ondansetron and ICS 205-930 but not by other receptor antagonists such as (+/-)-pindolol (a beta, 5-HT1A and 5-HT1B receptor antagonist), methy-sergide (a 5-HT1 and 5-HT2 receptor antagonist), ritanserin (a 5-HT1C and 5-HT2 receptor antagonist), SR 95103 (gamma-aminobutyric acidA receptor antagonist), scopolamine (a muscarinic antagonist), (-)-eticlopride (a D2 receptor antagonist), SCH 23390 (a D1 5-HT2/1C receptor antagonist) and prazosin (an alpha-1 receptor antagonist). In addition, the stimulation of PI turnover by 2-Me-5-HT was antagonized stereospecifically by the 5-HT3 receptor blocker zacopride. Thus, only the active enantiomer (S)-zacopride, but not the less active enantiomer (R)-zacopride, was effective in blocking the 2-Me-5-HT-induced effect.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of 5-hydroxytryptamine3 receptor agonists on phosphoinositides hydrolysis in the rat fronto-cingulate and entorhinal cortices. 184 25

Two subtypes of excitatory 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, are found on type 2-AH neurons of the guinea pig myenteric plexus. The 5-HT1P receptor mediates a slow and the 5-HT3 receptor a fast depolarization of these cells, however, the role of these receptors in the physiology of the gut is unknown. Renzapride (BRL 24924), a substituted benzamide, has previously been found to antagonize responses of myenteric neurons mediated by both 5-HT1P and 5-HT3 receptors. The effects on myenteric type 2-AH neurons of a structurally similar benzamide, zacopride, which unlike renzapride has S and R stereoisomers, were investigated to gain further insight into 5-HT receptor function. In contrast to renzapride, S-, but not R-zacopride, was found to mimic the 5-HT1P receptor-mediated slow response to 5-HT. Desensitization of 5-HT1P receptors with 5-HT inhibited slow depolarizing responses to S-zacopride, and desensitization with S-zacopride antagonized slow responses to 5-HT. Responses to S-zacopride were also inhibited by renzapride and the 5-HT1P receptor antagonist N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP). S-zacopride, like renzapride and 5-HT, presynaptically inhibited nicotinic fast excitatory postsynaptic potentials, an effect that can be mediated by 5-HT1P or 5-HT1A receptors. Both S and R stereoisomers of zacopride antagonized 5-HT3 receptor-mediated fast responses to 5-HT. Unlike 5-HTP-DP, neither zacopride or its stereoisomers nor renzapride inhibited the binding of 5-[3H]HT to 5-HT1P receptors. [3H]zacopride (5-10 nM) was found to bind to a site in the gut from which it could be displaced by a 1,000-fold excess of renzapride and S-zacopride (but not R-zacopride) greater than 5-HTP-DP much greater than the 5-HT3 receptor antagonist ICS 205-930. These observations suggest that, in addition to 5-HT3 receptors, there is a benzamide binding site on myenteric neurons that interacts with, but is distinct from, the 5-HT recognition site of 5-HT1P receptors. Benzamides may affect coupling of the 5-HT1P receptor to its effector.
 ...
PMID:Use of stereoisomers of zacopride to analyze actions of 5-hydroxytryptamine on enteric neurons. 198 11

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. 207 88

1. Neuronal 5-hydroxytryptamine (5-HT) receptors mediating contraction of guinea-pig ileal segments have been characterized in vitro by the use of methysergide to block 5-HT1-like and 5-HT2 receptors. Concentration-response curves to 5-HT were biphasic (first phase, defined as those responses occurring between 1 nM and 0.32 microM 5-HT, -log EC50 = 7.15 +/- 0.08; second phase, defined as these responses occurring between 0.32 microM and 32 microM 5-HT, -log EC50 = 5.32 +/- 0.03) but monophasic to 5-methoxytryptamine (-log EC50 = 7.0 +/- 0.08) and 2 methyl 5-HT (-log EC50 = 5.2 +/- 0.13). The maximal response of the first phase to 5-HT and the maximal response to 5-methoxytryptamine were 30 +/- 4% and 35 +/- 5% respectively of the maximum response to the second phase of the 5-HT concentration-effect curve (set at 100%). In contrast, the maximal response to 2-methyl-5-HT equalled that obtained with 5-HT (second phase). 2. The responses comprising the second phase of the concentration-effect curve to 5-HT were antagonized by 1 microM ICS 205-930, ondansetron, granisetron, quipazine, N-methyl-quipazine and (R,S)-zacopride and the following pKB values, with 5-HT as the agonist, were obtained at the 5-HT3 receptor: ICS 205-930 7.61 +/- 0.05, ondansetron 6.90 +/- 0.04, granisetron 7.90 +/- 0.04, (S)-zacopride 8.11 +/- 0.06, (R,S)-zacopride 7.64 +/- 0.11, and (R)-zacopride 7.27 +/- 0.06. 3. Under conditions of 5-HT1-like, 5-HT2 and 5-HT3 receptor blockade, the following rank order of agonism was observed: 5-HT > 5-methoxytryptamine = renzapride > (S)-zacopride > (R,S-zacopride > 5-carboxamidotryptamine > BRL 24682 > (R-zacopride > metoclopramide > 2-methyl-5-HT > sulpiride. 8-Dihydroxydiphenylaminotetralin (8-OHDPAT), GR 43175, N,N-dipropyl-5-carboxamidotryptamine, ondansetron, ICS 205-930, granisetron, quipazine and N-methyl-quipazine were inactive as agonists and antagonists. Relative to 5-HT, (R,S)-zacopride acted as a partial agonist (intrinsic activity, alpha = 0.80; -log EC50 = 6.3 + 0.12; -log KA = 6.1 + 0.03) as did (R)-zacopride (alpha = 0.4, -log EC,0 5.7 + 0.08, -log KA = 5.5 + 0.11). (S)-zacopride acted as a full agonist (-log EC,0 = 6.9 + 0.03). ICS 205-930 (3 microM) antagonized competitively responses to 5-HT, 5 methoxytryptamine, (RS)- and (S)- zacopride and 5-carboxamidotryptamine yielding -log KB estimates ranging from 6.1-6.5. 4. It is concluded that two different 5-HT receptors mediate excitatory neuronal responses in the guineapig ileum. 5-HT3 receptors mediate the second phase of the biphasic concentration-response curve, whereas a receptor with properties distinct from the 5-HT1-like, 5-HT2 and 5-HT3 subtypes mediates the initial phase of the concentration-response curve. This receptor, which exhibits a close similarity to the 5-HT4 subtype is: (1) stimulated by 5-methoxytryptamine but not 2-methyl-5-HT; (2) stimulated selectively by certain substituted benzamides; (3) recognizes the optical isomers of zacopride and (4) is blocked by relatively high concentrations ICS 205-930 (pKB = 6.0-6.5) but not ondansetron, granisetron, quipazine or N-methyl-quipazine.
 ...
PMID:Characterization of 5-HT3 and 'atypical' 5-HT receptors mediating guinea-pig ileal contractions in vitro. 207 74

In this study, we examined the effect of chronic administration of the selective 5-HT3 receptor antagonist BRL 43694 on the number of spontaneously active A9 (substantia nigra pars compacta) and A10 (ventral tegmental area) dopamine (DA) cells using the technique of extracellular single unit recording. Overall, chronic BRL 43694 (21 days, 5 mg/kg per day or 2.5 mg/kg q.i.d) failed to alter the number of spontaneously active DA cells in either area compared to saline-injected controls. Furthermore, the acute i.v. administration of BRL 43694 did not change A10 DA cell baseline firing rate. These data suggest that if BRL 43694 possesses antipsychotic activity, it is not the result of its action on midbrain DA neurons.
 ...
PMID:Chronic BRL 43694, a selective 5-HT3 receptor antagonist, fails to alter the number of spontaneously active midbrain dopamine neurons. 215 3


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