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)

The effects of 24 biguanide and four guanidine derivatives on 5-hydroxytryptamine (5-HT)3 receptors in N1E-115 neuroblastoma cells were examined using radioligand binding and whole-cell voltage-clamp techniques. Displacement of the selective 5-HT3 receptor antagonist [3H]BRL 43694 by phenylbiguanide (PBG) derivatives revealed Ki values ranging from 3.4 x 10(-4) to 4.4 x 10(-10) M. The rank order of potency of agonists was 2,3,5-trichloro-PBG > 2,3-dichloro-PBG = 2,5-dichloro-PBG = 3,5-dichloro-PBG > 3,4-dichloro-PBG = 3-chloro-PBG > 2-chloro-PBG = 4-chloro-PBG = 2-methyl-PBG = 2,4-difluoro-PBG > PBG = 2-trifluoro-5-chloro-PBG > 4-fluoro-PBG = 3-trifluoromethyl-PBG > 4-nitro-PBG = 1,5-bis-4-chloro-PBG = 3,5-ditrifluoromethyl-PBG > 4-ethoxy-PBG >> 4-sulfonic acid-PBG. All of the benzylbiguanides and indanylbiguanide were inactive on [3H]BRL 43694 binding or displaced it only weakly. The four guanidine derivatives were quite inactive. In the PBG series, all antagonist competition curves were steep (pseudo-Hill coefficients ranging from 1.05 to 1.58), monophasic, and best fit with a one-site model. Among PBG derivatives, the chlorinated compounds exhibited a good degree of selectivity for 5-HT3 receptors versus other 5-HT receptor subtypes and other neurotransmitter binding sites. Electrophysiological studies showed that the PBG derivatives tested produced rapid inward currents, at a holding potential of -65 mV, that showed rapid desensitization. The current induced by the 2,3,5-trichloro-PBG derivative was inhibited by the specific 5-HT3 receptor antagonist ICS 205-930 but was unaffected by the 5-HT2 receptor antagonist ketanserin. Analysis of concentration-response curves for the PBG derivatives gave EC50 values ranging from 2.2 x 10(-5) to 2.7 x 10(-8) M and Hill slopes ranging from 1.02 to 2.10. The rank order of potency was similar to that obtained from the binding data, and a good correlation was found between Ki and EC50 values. It is concluded that the triple-chloro substitution yielded a compound that is 30-fold more potent than 3-chloro-PBG and approximately 10-fold more potent than dichloro-PBG derivatives, making 2,3,5-trichloro-PBG the most potent 5-HT3 agonist described thus far.
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PMID:Biguanide derivatives: agonist pharmacology at 5-hydroxytryptamine type 3 receptors in vitro. 796 53

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

The influence of several imidazolines and sigma-site ligands on cation influx through the 5-HT3 receptor channel in N1E-115 mouse neuroblastoma cells was studied by measuring the 2-min influx of the organic cation [14C] guanidinium induced by 1 microM 5-HT (in the presence of 10 microM substance P in all experiments). In addition, we determined specific binding of [3H]DTG (1,3-di(2-tolyl)-guanidine), a selective sigma-site radioligand, and [3H] GR65630 (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1- propanone), a selective 5-HT3 receptor antagonist, to membranes prepared from N1E-115 cells. The 5-HT-induced [14C]guanidinium influx was inhibited by the imidazolines, ondansetron, antazoline, idazoxan, BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), cirazoline, naphazoline, clonidine and by the guanidine agmatine, but not by the catecholamine adrenaline. The inhibitory effect of the imidazolines on cation influx through the 5-HT3 receptor channel was mimicked by the sigma-site ligands, (+/-)-ifenprodil, (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-propylpiperidine), DTG (1,3-di-tolyl-guanidine). haloperidol, dizocilpine, and ketamine as well as by the polyamines, arcaine and spermidine.-Ondansetron inhibited [3H]GR65630 binding with high affinity, whereas inhibition of binding of this radioligand to the 5-HT3 receptor by antazoline, BDF 6143, idazoxan, cirazoline, (+/-)-ifenprodil, (+)-3-PPP, DTG and haloperidol occurred in the high micromolar range. In the competition experiments with [3H]DTG, (+/-)-ifenprodil, haloperidol, unlabelled DTG, BDF 6143 and (+)-3-PPP inhibited binding of the radioligand at moderate affinity (Ki values in the range of 1 microM or lower), whereas ondansetron, antazoline, idazoxan, cirazoline, naphazoline, clonidine, tolazoline, efaroxan, RX821002 (2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline), ketamine and spermidine exhibited affinity, in the high micromolar or millimolar range only. Comparison of the potencies of the ligands (pIC50% values) in inhibiting 5-HT-induced [14C]guanidinium influx with their affinities (pKi values) at the 5-HT recognition sites of the 5-HT3 receptor and at the sigma 2-sites of the N1E-115 cells by means of multiple regression analysis revealed a significant correlation with the affinities at both sites. In conclusion, our data suggest that imidazolines and sigma-ligands, which as a rule possess low affinity for the 5-HT recognition site of the 5-HT3 receptor, may be assumed to exert their inhibitory effect on cation influx through the 5-HT3 receptor channels, at least in part, by interacting with sigma 2-binding sites.
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PMID:Inhibition of 5-HT3 receptor function by imidazolines in mouse neuroblastoma cells: potential involvement of sigma 2 binding sites. 887 53