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

A series of aryl tropanyl esters and amides related to 1H-indole-3-carboxylic acid endo 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (ICS 205930, CAS 89565-68-4) were synthesized and evaluated for antinociceptive activity using the hot-plate test. Of these, the benzofurane-3-carboxylic ester of tropine (1) was found powerfully to increase the pain threshold, with a cholinergic mechanism of action. Despite the structural similarity with ICS 205930, the analgesia induced by 1 seems not to be due to 5-HT3 receptor interaction, and there is evidence of involvement of the central 5-HT4 receptor.
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PMID:Synthesis and biological activity of a series of aryl tropanyl esters and amides chemically related to 1H-indole-3-carboxylic acid endo 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester. Development of a 5-HT4 agonist endowed with potent antinociceptive activity. 821 52

A series of quinolinecarboxylic acid derivatives has been previously described as a new class of 5-HT3 receptor antagonists due to deviation of a carbonyl moiety from the place of an aromatic ring in their minimum-energy conformations. These derivatives were evaluated in a wrap-restraint stress-induced defecation model in rats. Reference compounds, ondansetron (1), granisetron (2), and YM060 (4), potently inhibited a stress-induced increase in stools excreted from fed rats (ID50 = 0.27, 0.12, and 0.0052 mg/kg, po, respectively). However, quinoline derivatives exhibited different activities depending on structural class. 4-Hydroxyquinoline-3-carboxylic acid derivatives 5 and 6a possess high affinity for the 5-HT3 receptor (Ki = 6.1 and 1.5 nM, respectively) and exhibit potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.0017 and 0.000 10 mg/kg, i.v., respectively), but they did not effectively inhibit the increase in fecal pellet output at the dose of 1 mg/kg, po. On the other hand, most of 1-substituted 2-oxoquinoline-4-carboxylates 10 showed less potent activity in the B-J reflex test than 1 or 2 but inhibited restraint stress-induced defecation more potently than 1 or 2. The ID50 value of endo-8-methyl-8- azabicyclo[3.2.1]oct-3-yl 1-isobutyl-2-oxo-1,2-dihydro-4- quinolinecarboxylate 10e was 0.013 mg/kg, po. With respect to the selected compounds 6a and 10e, effects of 5-HT- and thyrotropin-releasing hormone (TRH)-induced defecation, castor oil-induced diarrhea and wrap-restraint stress-induced colonic propulsion in rats were examined. These 5-HT3 receptor antagonists did not effectively inhibit castor oil-induced diarrhea, which has been reported not to be mediated via the 5-HT3 receptor. Although 10e showed 800-fold decreased potency compared with 4 in the B-J reflex test, 10e exhibited activity as potent as 4 in 5-HT- and TRH-induced defecation assays; 10e exhibited 7-fold increased potency compared with 4 in wrap-restraint stress-induced colonic propulsions. From these results, 10e appears to interact selectively with 5-HT3 receptors in the gastrointestinal system and might be effective in the therapy of irritable bowel syndrome (IBS).
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PMID:5-HT3 receptor antagonists. 3. Quinoline derivatives which may be effective in the therapy of irritable bowel syndrome. 823 Jan 19

The binding of [3H]endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)- 2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride ([3H]BIMU-1) a benzimidazolone with high affinity for 5-hydroxytryptamine (5-HT)3 and 4 5-HT3 and 5-HT4 receptors, was characterized in NG-108 cells and guinea pig hippocampus. Specific, heat-sensitive, binding of [3H]BIMU-1 was detected in both NG-108 cells and guinea pig hippocampus. In NG-108 cell membranes, a portion of the specific binding was displaced by 5-HT3 receptor ligands with affinities and specificity consistent with the labeling of 5-HT3 receptors. The residual specific binding was insensitive to serotonin (Ki > 1 mM) but was displaced by haloperidol (Ki of 50 nM). In guinea pig hippocampal membranes [3H]BIMU-1 binding was insensitive to serotonin but was displaced by haloperidol, and 1,3-di-o-tolyl-guanidine with affinities appropriate for the labeling of a sigma binding site (Ki of 6.3 and 31 nM, respectively). The affinity profile of ligands displacing [3H] BIMU-1 binding in guinea pig hippocampus was consistent with the selective labeling of a sigma-2 binding site because the sigma-1 selective benzomorphans, (+)-pentazocine and (+)-N-allylnormetazocine, only weakly displaced the binding (Ki greater than 1 microM). The affinity of BIMU-1 for sigma-2 binding sites (Ki = 32 nM) was 200-fold greater than that for sigma-1 binding sites (Ki = 6.3 microM), dopamine (D1 and D2), other serotonin (5-HT1A, 5-HT2A, 5-HT2C) and muscarinic (M1, M2, M3 and M4) receptors (Ki > 10 microM). The distribution of haloperidol-sensitive [3H]BIMU-1 binding was also consistent with the labeling of sigma-2 binding sites. These data suggest that [3H]BIMU-1 selectively labels sigma-2 binding sites in guinea pig hippocampus. [3H]BIMU-1, under appropriate experimental conditions, is thus the first sigma-2 binding site radioligand to be characterized.
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PMID:[3H]BIMU-1, a 5-hydroxytryptamine3 receptor ligand in NG-108 cells, selectively labels sigma-2 binding sites in guinea pig hippocampus. 824 71

A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromatic ring, but in 7 there was a 30 degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3- quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.1 micrograms/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: Ki = 0.48 nM) for the 5-HT3 receptors than ondansetron (Ki = 7.6 nM) or granisetron (Ki = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 micrograms/kg, iv) more potently than ondansetron (ED50 = 210 micrograms/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.
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PMID:5-HT3 receptor antagonists. 2. 4-Hydroxy-3-quinolinecarboxylic acid derivatives. 849 41

Intra- and extracellular recordings from the in vitro rat hippocampal slice preparation have been used to investigate the influence of serotoninergic, adrenergic and cholinergic receptor antagonists on the excitability of CA1 pyramidal neurones. The serotonin receptor antagonist 4-amino-N-(1-azabicyclo[2.2.2]oct-3yl)-5-chloro-2- methoxybenzamide(E)-2-butenedioate (zacopride, 100 microM) produced multiple population spikes on the orthodromically evoked field potential, in contrast to the lack of effect of another serotonin antagonist 1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222, 30 microM), as well as the cholinergic antagonists atropine (10 microM) and hexamethonium (100 microM) and the noradrenergic antagonist atenolol (10 microM). Monosynaptic inhibitory postsynaptic potentials (IPSPs) recorded in the presence of the glutamatergic antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and ketamine (50 microM) were recorded from CA1 pyramidal neurones. Zacopride (100 microM) and MDL 72222 (30 microM) both reduced the isolated IPSP to 54 +/- 9% (n = 8) and 78 +/- 4% (n = 3), respectively. Neither of the cholinergic antagonists had any effect, while atenolol reduced the IPSP to 87 +/- 3% (n = 7) of the control IPSP. We propose that the difference in action of zacopride and MDL 72222 on the field potentials is due to zacopride activating postsynaptic 5HT4 receptors on the pyramidal neurone, thereby reducing a Ca(2+)-activated K(+)-conductance. This, in combination with a 5HT3 receptor-mediated reduction in gamma-aminobutyric acid (GABA)-ergic inhibition, leads to an increase in pyramidal cell excitability evident as epileptic field potentials.
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PMID:Serotoninergic modulation of excitability in area CA1 of the in vitro rat hippocampus. 857

For imaging CNS 5-HT3 receptors by PET, a high affinity 5-HT3 receptor ligand, endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl 2-(n-propyloxy)-4-quinolinecarboxylate (KF17643), have been labeled with 11C. N-Methylation of the desmethyl compound with [11C]methyl iodide followed by HPLC separation produced [11C]KF17643 with the decay-corrected radiochemical yield of 19-28%, the specific activity of 7.5-49 GBq/mumol and the radiochemical purity of > 99% at 35-40 min from EOB. After i.v. injection of [11C]KF17643 into mice, it was taken by the brain at a high level and was stable for metabolism, but no sign for the 5-HT3 receptor selectivity was found in the brain tissues by the tissue sampling and autoradiography, probably because of large non-specific binding. The [11C]KF17643 was not suitable as a PET ligand for mapping the CNS 5-HT3 receptors.
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PMID:Synthesis and evaluation of 5-HT3 receptor antagonist [11C]KF17643. 878 38

Subcutaneous administration of granisetron (BRL 43694, endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl-1 H-indazole-3-carboxamide) and zacopride (4-amino-N-(1-azabicyclo[2.2.2.]oct-3-yl)-5-chloro-2-methoxybenzamide), two 5-HT3 receptor antagonists, at doses ranging from 3 to 1000 micrograms/kg, inhibited abdominal contractions induced by distension (30 mmHg, 10 min) of irritated colon (0.6% acetic acid) in conscious rats with a bell-shaped dose-response curve. The ED50 of granisetron and zacopride were 17.6 and 8.2 micrograms/kg, respectively. In contrast, both tropisetron (ICS 205-930, (3-a-tropanyl)t-indole-3-carboxylic ester) and ondansetron (GR38032F, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)methyl]-4 H-carbazol-4-one hydrocloride dihydrate) were inactive in this model. These data further support the concept of a heterogeneity in the potency of 5-HT3 receptor antagonists in modulating visceral hypersensitivity in conscious rats. This finding is in agreement with a reported efficacy of granisetron but not of ondansetron in patients with irritable bowel syndrome.
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PMID:Response heterogeneity of 5-HT3 receptor antagonists in a rat visceral hypersensitivity model. 900 25

The 5-hydroxytryptamine(HT)3 receptor subtype is present in the central nervous system (CNS) in low abundance, and few selective radiolabeled antagonists with high specific activity are available to study these sites. DAIZAC [desamino-3-iodo-(S)-zacopride; (S)-5-chloro-3-iodo-2-methoxy-N-(1-azobicyclo-[2.2. 2]oct-3-yl)benzamide] is a compound with high affinity and selectivity for the 5-HT3 receptor. Scatchard analysis of specific binding to NCB-20 cell membranes gave a Bmax of 340 +/- 58 fmol/mg protein and a KD of 0.14 +/- 0.03 nM, which is in agreement with the value previously reported in rat brain (KD = 0.15 nM). Nonspecific binding of [125I]DAIZAC in NCB-20 cells was <1% of total binding at the KD for DAIZAC compared with 17% in the rat brain preparation. Unlabeled DAIZAC (10 microM) showed minimal ability to displace binding of radiolabeled ligands selected for their affinities for other CNS receptor and uptake carrier binding sites. The discrimination ratio of DAIZAC for the 5-HT3 receptor over the M1 muscarinic binding site, the non-5-HT3 site at which it was most potent, was >2800. Serotonergic antagonists at every other known CNS serotonergic binding sites (3-30 microM) were ineffective in displacing [125I]DAIZAC binding in rat brain membranes. Similarly, antagonists (3-30 microM) for other nonserotonergic receptors and uptake sites were ineffective in displacing [125I]DAIZAC binding. Autoradiographic studies showed highest specific binding in area postrema and nucleus solitarius, with intermediate levels of binding in entorhinal cortex and hippocampus. DAIZAC inhibited 5-HT3 receptor-mediated inward cation current in NCB-20 cells with an IC50 of 0.24 nM. [125I]DAIZAC is a potent and highly selective ligand for in vitro studies of the 5-HT3 receptor.
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PMID:Characterization of (S)-des-4-amino-3-[125I]iodozacopride ([125I]DAIZAC), a selective high-affinity radioligand for 5-hydroxytryptamine3 receptors. 986 74

1. The in vitro hemisected spinal cord from young rat was used to investigate the mechanism of serotoninergic modulation of primary afferent-mediated synaptic transmission in the dorsal horn through activation of the 5-HT3 receptor. 2. Dorsal root-evoked excitatory post-synaptic potentials (DR-EPSPs) were recorded intracellularly from dorsal horn neurones. Extracellular recordings of the population primary afferent depolarization (PAD) and the dorsal root-evoked dorsal root reflex (DR-DRR) were made from segmental dorsal roots. 3. 5-Hydroxytryptamine (5-HT) and the selective 5-HT3 receptor agonist 1-(m-chloro-phenyl)-biguanide hydrochloride (m-ChPB) (10 and 50 microM) induced statistically significant reductions of the DR-EPSP amplitude (P<0.001) and duration (P<0.001) in the majority of dorsal horn neurones. The 5-HT3 receptor selective antagonists 3-Tropanyl-indole-3-carboxylate hydrochloride (Tropisetron, 10 microM) and N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carboxamide (Y-25130, 10 microM) abolished m-ChPB-induced DR-EPSP attenuation and partially blocked the 5-HT effect. 4. m-ChPB (50 microM)-induced DR-EPSP amplitude and duration attenuation was retained in the presence of the GABA(A) receptor antagonist bicuculline (30 microM), the GABA(B) receptor antagonist saclofen (50 microM) and the opioid receptor antagonist naloxone (50 microM). 5. Both 5-HT and m-ChPB (10 and 50 microM) induced a PAD but the mean peak amplitude of 5-HT-induced PAD was significantly greater than PAD to m-ChPB (98.6+/-12 microV compared to 51.8+/-10 V for 50 microM of agonist, respectively). Tropisetron partially reduced 5-HT-induced PAD and abolished m-ChPB-induced PAD. 5-HT, but not m-ChPB, significantly (P<0.001) reduced the peak amplitude of the DR-DRR and this action of 5-HT was unaffected by Tropisetron or Y-25130. 6. These data provide experimental evidence for a putative cellular mechanism at the level of the dorsal horn for anti-nociceptive effects of 5-HT3 receptor activation. This 5-HT3-mediated modulation of sensory afferent transmission was evidently independent of inhibitory GABA- or opioid-dependent interneuronal pathways. The extent to which the 5-HT3 receptor could be involved in the operation of endogenous analgesia and sensory modulation by descending monoamine bulbo-spinal pathways is discussed.
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PMID:Modulation of afferent-evoked neurotransmission by 5-HT3 receptors in young rat dorsal horn neurones in vitro: a putative mechanism of 5-HT3 induced anti-nociception. 1043 90

N(G)-(Nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in mice. The objective of the present work was to investigate if serotonergic drugs are able to modulate this effect. Results showed that the cataleptogenic effect of L-NOARG (40 mg/kg) in male albino-Swiss mice was enhanced by pre-treatment with (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY-100135, 5 or 10 mg/kg), a 5-HT1A-selective receptor antagonist, and by ketanserin (5 or 10 mg/kg), a 5-HT2A receptor and alpha1-adrenoceptor antagonist. Prazosin (3 or 5 mg/kg), an alpha1-adrenoceptor antagonist, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3yl)-2,3-dihydro-3,3-dimet hyl-indole-1-carboxamide HCl (BRL-46470A, 0.05 or 0.5 mg/kg), a 5-HT3 receptor antagonist, did not interfere with L-NOARG-induced catalepsy. Ritanserin (3 or 10 mg/kg), a 5-HT2A and 5-HT2C receptor antagonist, tended to enhance the effect of L-NOARG. These results confirm that interference with the formation of nitric oxide induces catalepsy in mice, and suggest that this effect is modulated by 5-HT1A and 5-HT2A receptors.
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PMID:Serotonin modulation of catalepsy induced by N(G)-nitro-L-arginine in mice. 1049 70


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