Palonosetron Exhibits Unique Molecular Interactions with the 5-HT3 Receptor

• DOI: 10.1213/ane.0b013e318172fa74
• Publication Date: 2009-03-05T20:18:53Z
• Authors: Camilo Rojas; Marigo Stathis; Ajit G. Thomas; Edward B. Massuda; Jesse Alt; Jie Zhang; Ed Rubenstein; Silvia Sebastiani; Sergio Cantoreggi; Solomon H. Snyder; Barbara Slusher
• Keywords: Palonosetron; Granisetron; Ondansetron; 5-HT3 receptor

In Brief BACKGROUND: Palonosetron is a 5-HT3-receptor antagonist (5-HT3-RA) that has been shown to be superior other 5-HT3-RAs in phase III clinical trials for the prevention of acute, delayed, and overall chemotherapy-induced nausea vomiting. The improved efficacy palonosetron may due, part, its more potent binding longer half-life. However, these attributes alone are not sufficient explain results with palonosetron. We sought elucidate additional differences among could help observations clinic. METHODS: Receptor site saturation experiments were performed [3H] palonosetron, granisetron, ondansetron obtain corresponding Scatchard analyses Hill coefficients. Diagnostic equilibrium kinetic dissociation conducted examine competitive versus potential allosteric interactions between ondansetron, granisetron 5-HT3 receptor. Finally, long-term effect three antagonists on receptor function as measured by Ca2+ influx HEK 293 cells expressing was compared. RESULTS: Analyses isotherms using both plots suggested positive cooperativity simple bimolecular ondansetron. Equilibrium diagnostic tests discriminated differential effects ligand indicating an whereas antagonists. Using rate strategies, modifier accelerated from Differences mode have impact function. experiments, incubated each antagonist, followed infinite dilutions 2.5 h; previously either or showed calcium-ion similar control had exposed antagonist. contrast, substantial inhibition observed CONCLUSIONS: exhibited when also triggered functional persisted beyond at cell surface. relevant unique beneficial actions To our knowledge, this first report showing palonosetron's interaction molecular level, clearly differentiating it 5-HT3-RAs. IMPLICATIONS: exhibits Palonosetron's combined properties binding, cooperativity, make distinctive within class.