5-HT3 Antagonist - History

History

The history of the 5-HT₃ receptor antagonists began in 1957, when J.H. Gaddum and Zuleika P. Picarelli at the University of Edinburgh proposed the existence of two serotonin receptor subtypes, the M and D receptors (thus named because their function could be blocked by morphine and Dibenzyline respectively), in a landmark paper. The 5-HT₃ receptor was later found to correspond to the M receptor. In the 1970s, John Fozard proved that metoclopramide and cocaine were weak antagonists at the 5-HT₃ (5-HT-M) receptor. Fozard and Maurice Gittos later synthesized MDL 72222, the first potent and truly selective 5-HT₃ receptor antagonist. The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism.

While Fozard was investigating cocaine analogues, workers at Sandoz identified the potent, selective 5-HT₃ receptor antagonist ICS 205-930 from which the first marketed selective 5-HT₃ receptor antagonists ondansetron and granisetron were developed, and approved in 1991 and 1993 respectively. Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997. A new and improved 5-HT₃ receptor antagonist, named palonosetron, was approved in 2003. The development of selective 5-HT₃ receptor antagonists was a dramatic improvement in the treatment of nausea and vomiting. Ondansetron, granisetron, dolasetron and palonosetron are currently approved in the United States, and form the cornerstone of therapy for the control of acute emesis with chemotherapy agents with moderate to high emetogenic potential.