The Pharmacology of TD-8954, a Potent and Selective 5-HT4 Receptor Agonist with Gastrointestinal Prokinetic Properties

This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT 4 receptor agonist. TD-8954 had high affinity (pK i = 9.4) for human recombinant 5-HT 4(c) (h5-HT 4(c) ) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested ( n = 78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT 4(c) receptor (pEC 50 = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC 50 = 8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03–3 mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03–10 mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD-8954 (10 and 30 μg/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1–20 mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT 4 receptor agonist in vitro , with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility.