title: The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties.
abstract: 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.
authors.affiliation: Department of Pharmacology, Theravance, Inc. South San Francisco, CA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Beattie
authors.forename: Scott R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: Ross G
authors.initials: RG
authors.lastname: Vickery
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tsuruda
authors.forename: Christina B
authors.initials: CB
authors.lastname: Campbell
authors.forename: Carrie
authors.initials: C
authors.lastname: Richardson
authors.forename: Julia L
authors.initials: JL
authors.lastname: McCullough
authors.forename: Oranee
authors.initials: O
authors.lastname: Daniels
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kersey
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Karl H S
authors.initials: KH
authors.lastname: Kim