Translating 5-HT receptor pharmacology.

Abstract

Since metoclopramide was first described (in 1964) there have been several attempts to develop compounds which retained gastrointestinal prokinetic activity (via 5-HT(4) receptor activation) but without the limiting side effects associated with dopamine D(2) receptor antagonism. Early compounds (mosapride, cisapride, renzapride, tegaserod) were identified before several of the 5-HT receptors were even described (including 5-HT(4) and 5-HT(2B)), whereas prucalopride came later. Several compounds were hampered by non-selectivity, introducing cardiac liability (cisapride: activity at human Ether-a-go-go Related Gene) or potentially, a reduced intestinal prokinetic activity caused by activity at a second 5-HT receptor (renzapride: antagonism at the 5-HT(3) receptor; tegaserod: antagonism at the 5-HT(2B) receptor). Poor intrinsic activity at gastrointestinal 5-HT(4) receptors has also been an issue (mosapride, tegaserod). Perhaps prucalopride has now achieved the profile of good selectivity of action and high intrinsic activity at intestinal 5-HT(4) receptors, without clinically-meaningful actions on 5-HT(4) receptors in the heart. The progress of this compound for treatment of chronic constipation, as well as competitor molecules such as ATI-7505 and TD-5108, will now be followed with interest as each attempts to differentiate themselves from each other. Perhaps at last, 5-HT(4) receptor agonists are being given the chance to show what they can do.

• Authors: G J Sanger
• Journal: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (Neurogastroenterol Motil) Vol. 21 Issue 12 Pg. 1235-8 (Dec 2009) ISSN: 1365-2982 [Electronic] England
• PMID: 19906028 (Publication Type: Journal Article, Review)

Chemical References

• Benzofurans
• Dopamine Antagonists
• Receptors, G-Protein-Coupled
• Serotonin 5-HT4 Receptor Agonists
• Serotonin Receptor Agonists
• prucalopride
• Receptors, Serotonin, 5-HT4
• Metoclopramide

Topics

• Aged
• Animals
• Benzofurans (adverse effects, pharmacology, therapeutic use)
• Dopamine Antagonists (pharmacology, therapeutic use)
• Gastrointestinal Diseases (drug therapy, physiopathology)
• Gastrointestinal Motility (drug effects)
• Humans
• Metoclopramide (pharmacology, therapeutic use)
• Receptors, G-Protein-Coupled (drug effects)
• Receptors, Serotonin, 5-HT4 (drug effects)
• Serotonin 5-HT4 Receptor Agonists
• Serotonin Receptor Agonists (adverse effects, pharmacology, therapeutic use)