Research article

Functional group interactions of a 5-HT₃R antagonist

Padmavati Venkataraman² , Prasad Joshi¹ , Srinivasan P Venkatachalan¹ , Mani Muthalagi¹ , Harish S Parihar¹ , Karen S Kirschbaum¹ and Marvin K Schulte¹

¹  Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209, USA

²  Department of Neurobiology and Physiology Northwestern University Evanston, IL 60208-3520, USA

author email corresponding author email

BMC Biochemistry 2002, 3:16doi:10.1186/1471-2091-3-16

Published:	13 June 2002

Abstract

Background

Lerisetron, a competitive serotonin type 3 receptor (5-HT₃R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT₃R binding site. Site directed mutagenesis studies of the 5-HT_3AR 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-HT₃R 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_3ASRs. 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_3ASR. 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.