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Titolo:
Binding characteristics of GYKI-46 903, a non-competitive ligand at 5-HT3 receptors
Autore:
Vitalis, B; Sebestyen, L; Sike, M; Solyom, S; Harsing, LG;
Indirizzi:
Inst Drug Res Ltd, H-1045 Budapest, Hungary Inst Drug Res Ltd Budapest Hungary H-1045 Ltd, H-1045 Budapest, Hungary
Titolo Testata:
PHARMACOLOGICAL RESEARCH
fascicolo: 3, volume: 43, anno: 2001,
pagine: 291 - 299
SICI:
1043-6618(200103)43:3<291:BCOG9A>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
NCB-20 NEUROBLASTOMA-CELLS; SEROTONIN 5HT(3) RECEPTOR; NODOSE GANGLION NEURONS; GATED ION-CHANNEL; ALLOSTERIC INTERACTIONS; MUSCARINIC RECEPTORS; RECOGNITION SITES; 5-HYDROXYTRYPTAMINE(3) RECEPTOR; ACETYLCHOLINE-RECEPTOR; RADIOLIGAND BINDING;
Keywords:
5-HT3 receptor; [H-3]granisetron; non-competitive and allosteric;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
66
Recensione:
Indirizzi per estratti:
Indirizzo: Harsing, LG Inst Drug Res Ltd, 47-49 Berlini Ut, H-1045 Budapest, Hungary Inst Drug Res Ltd 47-49 Berlini Ut Budapest Hungary H-1045 ry
Citazione:
B. Vitalis et al., "Binding characteristics of GYKI-46 903, a non-competitive ligand at 5-HT3 receptors", PHARMAC RES, 43(3), 2001, pp. 291-299

Abstract

GYKI-46903 [(+)-(5s,6R)-4-(4-fluorophenyl)-6-propionyloxy-1-aza-bicyclo[3.3.1]-non-3-ene-hydrochloride]. a cognition enhancer identified as a non-competitive antagonist of 5-HT3 receptors in isolated guinea-pig ileum, was investigated for allosteric action at 5-HT3 receptors in rat cortical membranes by using [H-3]granisetron. Equilibrium and kinetic protocols were applied and the competitive antagonist granisetron was included as a negative control. In competition studies, both granisetron and GYKI-46 903 displaced the radioligand with K-i values of 0.20 +/- 0.02 and 79.84 +/- 0.28 nM, respectively. The inhibition curve for GYKI-46 903 resulted in a Hill slope significantly greater than unity (1.37 +/- 0.11), whereas the slope for granisetron was 0.88 +/- 0.08, not different from unity. These results indicate non-competitive and competitive interactions, respectively. Scatchard analysis yielded a linear plot, suggesting a single population of binding sites with a K-d of 0.13 +/- 0.01 nM and a B-max of 13.15 +/- 0.34 fmol per mg of protein. Scatchard plots obtained in the absence and presence of granisetron(0.1-3 nM) or GYKI-46 903 (30-1000 nM) revealed a concentration-dependent increase in K-d values by either of these compounds. Granisetron left the B-max unchanged, but there was a significant increase in the B-max by GYKI-46 903, which could point to an atypical allosteric interaction. The Schild plot derived from the K-d shifts induced by granisetron was linear with a slope of 1.02, not different from unity. as expected from a competitive interaction. The Schild regression for GYKI-46 903 was linear with a slope of 1.20. deviating significantly from unity, which may also indicate an allosteric interaction. Both the association and dissociation curves of [H-3]granisetron were monoexponential. The dissociation rate constant (K-1) and the association rare constant (K+1) were 0.32 +/- 0.01 min(-1) and 1.15 min(-1) nM(-1), respectively. The dissociation driven by an excess concentration ofondansetron (1 muM) in the absence and presence of granisetron (0.1-3 nM) or GYKI-46 903 (30-10 000 nM) was not influenced by the compounds under study, as compared with the control, indicating the lack of an allosteric effect on the dissociation. Summing up, the binding profile of GYKI-46 903 may reflect a mixed type of action, including a negative allosteric interaction. (C) 2001 Academic Press.

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Documento generato il 07/04/20 alle ore 22:51:47