Metoclopramide: A Template for Drug Discovery

Metoclopramide was described in 1964 as an anti-emetic drug and stimulant of gastrointestinal motility. Dopamine D2 receptor antagonism explained the anti-emetic activity and was suggested to stimulate gastrointestinal motility. An important use of metoclopramide and other D2 receptor antagonists is to inhibit emesis caused by anticancer chemo radiotherapy. However, the use of new platinum-based anti-cancer drugs led to debilitating emesis, lasting for days and sometimes leading to refusal of treatment. Unlike conventional doses, higher doses of metoclopramide inhibited this severe emesis whereas subsequent trials with higher doses of other D2 receptor antagonists were unsuccessful. Studies using ferrets replicated these findings and then demonstrated the ability of 5-HT3 receptor antagonists to inhibit cisplatin-induced emesis, correlating with the known ability of higher concentrations of metoclopramide to antagonise at this receptor. Around the same time, the mechanism by which metoclopramide stimulates GI motility was shown to be independent of D2 and 5-HT3 receptor antagonism. A ‘myenteric 5-HT-like receptor’ was proposed, mediating the ability of metoclopramide to facilitate GI cholinergic activity. Later, this was characterised as the 5-HT4 receptor. Extensive drug discovery followed the unravelling of the biology of metoclopramide. The serendipitous discovery of this drug has therefore contributed to development of three new drug classes: selective (peripherally-restricted) antagonists at D2 and 5-HT3 receptors and selective agonists at the 5-HT4 receptor. The latter are used to treat idiopathic constipation. 5-HT3 receptor antagonists, together with dexamethasone and if necessary, NK1 receptor antagonists, prevent moderate-to-severe emesis during anti-cancer treatment and hence, began a revolution in cancer patient care. The ability of 5-HT3 receptor antagonists to cause mild constipation was used to treat diarrhoeapredominant irritable bowel syndrome, achieving clinical success but later associated with severe adverse events. Antagonists at the D2 receptor treat mild forms of emesis. Metoclopramide is still used as a gastric prokinetic and anti-emetic drug.