title: Functional group interactions of a 5-HT3R antagonist.
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-HT3AR 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-HT3ASRs. 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-HT3ASR. 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.
authors.affiliation: Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208-3520, USA. padma964@hotmail.com
authors.forename: Padmavati
authors.initials: P
authors.lastname: Venkataraman
authors.forename: Prasad
authors.initials: P
authors.lastname: Joshi
authors.forename: Srinivasan P
authors.initials: SP
authors.lastname: Venkatachalan
authors.forename: Mani
authors.initials: M
authors.lastname: Muthalagi
authors.forename: Harish S
authors.initials: HS
authors.lastname: Parihar
authors.forename: Karen S
authors.initials: KS
authors.lastname: Kirschbaum
authors.forename: Marvin K
authors.initials: MK
authors.lastname: Schulte
mesh_terms: D000818:Animals; D001120:Arginine / Q000502:physiology; D001562:Benzimidazoles / Q000378:metabolism; D001593:Benzyl Compounds / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D051379:Mice; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009584:Nitrogen / Q000378:metabolism; D018408:Patch-Clamp Techniques; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping / Q000379:methods*; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000502:physiology; D014443:Tyrosine / Q000502:physiology
chemical_list: D001562:Benzimidazoles; D001593:Benzyl Compounds; D010879:Piperazines; D010880:Piperidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D000077489:Piperazine; D014443:Tyrosine; D014364:Tryptophan; D001120:Arginine; D009584:Nitrogen; C115094:lerisetron