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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.


Related in: MedlinePlus

Dose-dependent relaxation [mean (±SEM) change in inter-crystal distance (in mm)] of the rat esophagus following i.d. administration of TD-8954 (0.03–10 mg/kg; n = 4), prucalopride (0.03–10 mg/kg; n = 4), tegaserod (0.03–10 mg/kg; n = 6), cisapride (0.3–10 mg/kg; n = 4), and mosapride (0.3–10 mg/kg; n = 4).
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Figure 4: Dose-dependent relaxation [mean (±SEM) change in inter-crystal distance (in mm)] of the rat esophagus following i.d. administration of TD-8954 (0.03–10 mg/kg; n = 4), prucalopride (0.03–10 mg/kg; n = 4), tegaserod (0.03–10 mg/kg; n = 6), cisapride (0.3–10 mg/kg; n = 4), and mosapride (0.3–10 mg/kg; n = 4).

Mentions: Following crystal placement on the rat esophagus, 30 min proved sufficient to establish a stable sonomicrometry recording. No spontaneous changes in esophageal muscle length were observed after this stabilization period. Following cumulative i.d. dosing, TD-8954, prucalopride, tegaserod (each 0.03–10 mg/kg), cisapride (0.3–10 mg/kg), and mosapride (0.3–10 mg/kg), but not their vehicles (1–10 mL/kg) evoked a dose-dependent increase in inter-crystal distance, consistent with esophageal relaxation (Figure 4). The ED50 values (with 95% confidence limits) for TD-8954 and prucalopride were 0.15 (0.08–0.26) and 0.18 (0.13–0.25) mg/kg, respectively. Accurate ED50 values could not be calculated for tegaserod, cisapride, and mosapride as solubility limitations precluded verification that their maximum relaxations had been achieved. To compare the potencies of each compound, the doses of TD-8954, prucalopride, tegaserod, cisapride, and mosapride associated with a relaxation response of 0.1 mm were calculated (i.e., 0.23, 0.30, 2.43, 2.66, and 4.37 mg/kg, respectively; Figure 4). TD-8954 was therefore equieffective, on a dose basis, with prucalopride following i.d. dosing, and 11-, 12-, and 19-fold more potent than tegaserod, cisapride, and mosapride, respectively.


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)

Dose-dependent relaxation [mean (±SEM) change in inter-crystal distance (in mm)] of the rat esophagus following i.d. administration of TD-8954 (0.03–10 mg/kg; n = 4), prucalopride (0.03–10 mg/kg; n = 4), tegaserod (0.03–10 mg/kg; n = 6), cisapride (0.3–10 mg/kg; n = 4), and mosapride (0.3–10 mg/kg; n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Dose-dependent relaxation [mean (±SEM) change in inter-crystal distance (in mm)] of the rat esophagus following i.d. administration of TD-8954 (0.03–10 mg/kg; n = 4), prucalopride (0.03–10 mg/kg; n = 4), tegaserod (0.03–10 mg/kg; n = 6), cisapride (0.3–10 mg/kg; n = 4), and mosapride (0.3–10 mg/kg; n = 4).
Mentions: Following crystal placement on the rat esophagus, 30 min proved sufficient to establish a stable sonomicrometry recording. No spontaneous changes in esophageal muscle length were observed after this stabilization period. Following cumulative i.d. dosing, TD-8954, prucalopride, tegaserod (each 0.03–10 mg/kg), cisapride (0.3–10 mg/kg), and mosapride (0.3–10 mg/kg), but not their vehicles (1–10 mL/kg) evoked a dose-dependent increase in inter-crystal distance, consistent with esophageal relaxation (Figure 4). The ED50 values (with 95% confidence limits) for TD-8954 and prucalopride were 0.15 (0.08–0.26) and 0.18 (0.13–0.25) mg/kg, respectively. Accurate ED50 values could not be calculated for tegaserod, cisapride, and mosapride as solubility limitations precluded verification that their maximum relaxations had been achieved. To compare the potencies of each compound, the doses of TD-8954, prucalopride, tegaserod, cisapride, and mosapride associated with a relaxation response of 0.1 mm were calculated (i.e., 0.23, 0.30, 2.43, 2.66, and 4.37 mg/kg, respectively; Figure 4). TD-8954 was therefore equieffective, on a dose basis, with prucalopride following i.d. dosing, and 11-, 12-, and 19-fold more potent than tegaserod, cisapride, and mosapride, respectively.

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.


Related in: MedlinePlus