Abstract
This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT4 receptor agonist. TD-8954 had high affinity (pKi = 9.4) for human recombinant 5-HT4(c) (h5-HT4(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-HT4(c) receptor (pEC50 = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC50 = 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-HT4 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.
Highlights
5-Hydroxytryptamine (5-HT) plays a critical role in coordinating gastrointestinal (GI) transit (Hansen and Skadhauge, 1997; Grider et al, 1998; Jin et al, 1999; Baker, 2005)
In response to intestinal stretching and mucosal stimulation, 5-HT is released from enterochromaffin cells of the mucosal epithelium, and promotes peristalsis via activation of intrinsic primary afferent neurons located in the submucous plexus (Kirchgessner et al, 1992; FoxxOrenstein et al, 1995; Gershon and Tack, 2007)
The peristaltic reflex, for example, is dependent on activation of 5-HT4 receptors on intrinsic primary afferent neurons, interneurons, and motor neurons within the gut wall, which results in the coordinated release of acetylcholine, substance P, and calcitonin gene-related peptide
Summary
All animal experiments were conducted in accordance with the principles of good laboratory animal care provided by the Institutional Animal Care and Use Committees of Theravance, Inc. (rodent studies) or Drug Research Laboratories (dog study). GUINEA PIG COLONIC TRANSIT Adult, male Dunkin Hartley guinea pigs (220–300 g, Harlan, Chicago, IL, USA) were acclimated to their holding room (temperature controlled at 21 ± 1 ̊C and 12:12 h light–dark cycle commencing at 7 a.m.) for approximately 1 week prior to surgery. Animals were dosed with test agent or vehicle (2 mL/kg s.c.), and 5 min later, each guinea pig was gently restrained and a non-absorbable marker (0.2 mL) was infused into the proximal colon via the implanted cannula. After recording data for a full motility cycle, and confirming commencement of a quiescent period, each dog was dosed orally with TD-8954 (0.01 and 0.03 mg/kg), tegaserod (0.1 and 0.3 mg/kg), or vehicle (1 mL/kg over 5 s), followed by a 10 mL flush of water. Doses were expressed with respect to the free base weights of each compound
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