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Functional group interactions of a 5-HT(3)R antagonist

BACKGROUND: Lerisetron, a competitive serotonin type 3 receptor (5-HT(3)R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT(3)R binding site. Site directed mutagenesis studies of the 5-HT(3A)R have revealed several amino acids that are thought to form p...

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Autores principales: Venkataraman, Padmavati, Joshi, Prasad, Venkatachalan, Srinivasan P, Muthalagi, Mani, Parihar, Harish S, Kirschbaum, Karen S, Schulte, Marvin K
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC116678/
https://www.ncbi.nlm.nih.gov/pubmed/12079499
http://dx.doi.org/10.1186/1471-2091-3-16
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author Venkataraman, Padmavati
Joshi, Prasad
Venkatachalan, Srinivasan P
Muthalagi, Mani
Parihar, Harish S
Kirschbaum, Karen S
Schulte, Marvin K
author_facet Venkataraman, Padmavati
Joshi, Prasad
Venkatachalan, Srinivasan P
Muthalagi, Mani
Parihar, Harish S
Kirschbaum, Karen S
Schulte, Marvin K
author_sort Venkataraman, Padmavati
collection PubMed
description BACKGROUND: Lerisetron, a competitive serotonin type 3 receptor (5-HT(3)R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT(3)R binding site. Site directed mutagenesis studies of the 5-HT(3A)R have revealed several amino acids that are thought to form part of the binding domain of this receptor. The specific functional groups on the ligand that interact with these amino acids are, however, unknown. Using synthetic analogs of lerisetron as molecular probes in combination with site directed mutagenesis, we have identified some of these interactions and have proposed a model of the lerisetron binding site. RESULTS: Two analogs of lerisetron were synthesized to probe 5-HT(3)R functional group interactions with this compound. Analog 1 lacks the N1 benzyl group of lerisetron and analog 2 contains oxygen in place of the distal piperazine nitrogen. Both analogs show significantly decreased binding affinity to wildtype 5-HT(3AS)Rs. Mutations at W89, R91, Y142 and Y152 produced significant decreases in binding compared to wildtype receptors. Binding affinities of analogs 1 and 2 were altered only by mutations at W89, and Y152. CONCLUSIONS: Based on the data obtained for lerisetron and analogs 1 and 2, we have proposed a tentative model of the lerisetron binding pocket of the 5-HT(3AS)R. According to this model, The N-benzyl group interacts in a weak interaction with R91 while the benzimidazole group interacts with W89. Our data support an interaction of the distal amino nitrogen with Y142 and Y152.
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spelling pubmed-1166782002-07-05 Functional group interactions of a 5-HT(3)R antagonist Venkataraman, Padmavati Joshi, Prasad Venkatachalan, Srinivasan P Muthalagi, Mani Parihar, Harish S Kirschbaum, Karen S Schulte, Marvin K BMC Biochem Research Article BACKGROUND: Lerisetron, a competitive serotonin type 3 receptor (5-HT(3)R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT(3)R binding site. Site directed mutagenesis studies of the 5-HT(3A)R have revealed several amino acids that are thought to form part of the binding domain of this receptor. The specific functional groups on the ligand that interact with these amino acids are, however, unknown. Using synthetic analogs of lerisetron as molecular probes in combination with site directed mutagenesis, we have identified some of these interactions and have proposed a model of the lerisetron binding site. RESULTS: Two analogs of lerisetron were synthesized to probe 5-HT(3)R functional group interactions with this compound. Analog 1 lacks the N1 benzyl group of lerisetron and analog 2 contains oxygen in place of the distal piperazine nitrogen. Both analogs show significantly decreased binding affinity to wildtype 5-HT(3AS)Rs. Mutations at W89, R91, Y142 and Y152 produced significant decreases in binding compared to wildtype receptors. Binding affinities of analogs 1 and 2 were altered only by mutations at W89, and Y152. CONCLUSIONS: Based on the data obtained for lerisetron and analogs 1 and 2, we have proposed a tentative model of the lerisetron binding pocket of the 5-HT(3AS)R. According to this model, The N-benzyl group interacts in a weak interaction with R91 while the benzimidazole group interacts with W89. Our data support an interaction of the distal amino nitrogen with Y142 and Y152. BioMed Central 2002-06-13 /pmc/articles/PMC116678/ /pubmed/12079499 http://dx.doi.org/10.1186/1471-2091-3-16 Text en Copyright © 2002 Venkataraman et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
spellingShingle Research Article
Venkataraman, Padmavati
Joshi, Prasad
Venkatachalan, Srinivasan P
Muthalagi, Mani
Parihar, Harish S
Kirschbaum, Karen S
Schulte, Marvin K
Functional group interactions of a 5-HT(3)R antagonist
title Functional group interactions of a 5-HT(3)R antagonist
title_full Functional group interactions of a 5-HT(3)R antagonist
title_fullStr Functional group interactions of a 5-HT(3)R antagonist
title_full_unstemmed Functional group interactions of a 5-HT(3)R antagonist
title_short Functional group interactions of a 5-HT(3)R antagonist
title_sort functional group interactions of a 5-ht(3)r antagonist
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC116678/
https://www.ncbi.nlm.nih.gov/pubmed/12079499
http://dx.doi.org/10.1186/1471-2091-3-16
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