title: 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.affiliation: Wingate Institute of Neurogastroenterology, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. g.sanger@qmul.ac.uk
authors.forename: G J
authors.initials: GJ
authors.lastname: Sanger
mesh_terms: D000368:Aged; D000818:Animals; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D008787:Metoclopramide / Q000494:pharmacology / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects*; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001572:Benzofurans; D018492:Dopamine Antagonists; D043562:Receptors, G-Protein-Coupled; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D008787:Metoclopramide