AUTHOR=Beattie David T., Armstrong Scott R., Vickery Ross G., Tsuruda Pam , Campbell Christina B., Richardson Carrie , McCullough Julia , Daniels Oranee , Kersey Kathryn , Li Yu-Ping , Kim Karl H.

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

JOURNAL=Frontiers in Pharmacology

VOLUME=2

YEAR=2011

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2011.00025

DOI=10.3389/fphar.2011.00025

ISSN=1663-9812

ABSTRACT=<p>This study evaluated the <italic>in vitro</italic> and <italic>in vivo</italic> pharmacological properties of TD-8954, a potent and selective 5-HT<sub>4</sub> receptor agonist. TD-8954 had high affinity (pK<sub>i</sub> = 9.4) for human recombinant 5-HT<sub>4(c)</sub> (h5-HT<sub>4(c)</sub>) receptors, and selectivity (&gt;2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (<italic>n</italic> = 78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT<sub>4(c)</sub> receptor (pEC<sub>50</sub> = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC<sub>50</sub> = 8.6). TD-8954 had moderate intrinsic activity in the <italic>in vitro</italic> 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<sub>4</sub> receptor agonist <italic>in vitro</italic>, with robust <italic>in vivo</italic> 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.</p>