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The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties.

Beattie DT, Armstrong SR, Vickery RG, Tsuruda PR, Campbell CB, Richardson C, McCullough JL, Daniels O, Kersey K, Li YP, Kim KH - Front Pharmacol (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Theravance, Inc. South San Francisco, CA, USA.

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.

No MeSH data available.


The effects of TD-8954, tegaserod, cisapride, mosapride (each at 0.03–3 mg/kg), prucalopride (0.03–10 mg/kg), and vehicle (2 mL/kg), administered s.c., on the colonic transit of dye in conscious guinea pigs (n = 9–22 for each group; *p < 0.05; ANOVA followed by Dunnett’s post hoc test vs. vehicle).
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Figure 3: The effects of TD-8954, tegaserod, cisapride, mosapride (each at 0.03–3 mg/kg), prucalopride (0.03–10 mg/kg), and vehicle (2 mL/kg), administered s.c., on the colonic transit of dye in conscious guinea pigs (n = 9–22 for each group; *p < 0.05; ANOVA followed by Dunnett’s post hoc test vs. vehicle).

Mentions: In vehicle (2 mL/kg s.c.)-treated guinea pigs, the mean time taken for excretion of the first fecal pellet containing red dye was typically between 220 and 310 min. Following s.c. dosing, TD-8954, tegaserod, cisapride, mosapride (each at 0.03–3 mg/kg) and prucalopride (0.03–10 mg/kg) increased colonic transit, reducing the time taken for excretion of the dye, compared to vehicle-treated animals (Figure 3), although statistical significance (p < 0.05, one-way ANOVA with a Dunnett’s post hoc test) was achieved only for all of the TD-8954 doses and for the 0.3 and 3 mg/kg prucalopride doses. TD-8954 was more potent than tegaserod, prucalopride, cisapride, and mosapride, being significantly active at the lowest dose tested (0.03 mg/kg). At 0.03 mg/kg, TD-8954 had already achieved its maximum effect.


The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties.

Beattie DT, Armstrong SR, Vickery RG, Tsuruda PR, Campbell CB, Richardson C, McCullough JL, Daniels O, Kersey K, Li YP, Kim KH - Front Pharmacol (2011)

The effects of TD-8954, tegaserod, cisapride, mosapride (each at 0.03–3 mg/kg), prucalopride (0.03–10 mg/kg), and vehicle (2 mL/kg), administered s.c., on the colonic transit of dye in conscious guinea pigs (n = 9–22 for each group; *p < 0.05; ANOVA followed by Dunnett’s post hoc test vs. vehicle).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108484&req=5

Figure 3: The effects of TD-8954, tegaserod, cisapride, mosapride (each at 0.03–3 mg/kg), prucalopride (0.03–10 mg/kg), and vehicle (2 mL/kg), administered s.c., on the colonic transit of dye in conscious guinea pigs (n = 9–22 for each group; *p < 0.05; ANOVA followed by Dunnett’s post hoc test vs. vehicle).
Mentions: In vehicle (2 mL/kg s.c.)-treated guinea pigs, the mean time taken for excretion of the first fecal pellet containing red dye was typically between 220 and 310 min. Following s.c. dosing, TD-8954, tegaserod, cisapride, mosapride (each at 0.03–3 mg/kg) and prucalopride (0.03–10 mg/kg) increased colonic transit, reducing the time taken for excretion of the dye, compared to vehicle-treated animals (Figure 3), although statistical significance (p < 0.05, one-way ANOVA with a Dunnett’s post hoc test) was achieved only for all of the TD-8954 doses and for the 0.3 and 3 mg/kg prucalopride doses. TD-8954 was more potent than tegaserod, prucalopride, cisapride, and mosapride, being significantly active at the lowest dose tested (0.03 mg/kg). At 0.03 mg/kg, TD-8954 had already achieved its maximum effect.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Theravance, Inc. South San Francisco, CA, USA.

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.

No MeSH data available.