Limits...
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

Contractile activity following oral dosing of TD-8954 (0.01 and 0.03 mg/kg; n = 5; left-hand columns), tegaserod (0.1 and 0.3 mg/kg; n = 6; right-hand columns), and vehicles (n = 5 or 6) in the canine antrum, duodenum, and jejunum. Data are expressed as the mean (±SEM) cumulative contractile AUC in 10-min periods for 3 h post-dosing (at 0 min). Data are analyzed using a two-way analysis of variance with a Bonferroni post hoc test (*,#p < 0.05 for the 0.01, 0.03, and 0.3 mg/kg treatment groups, respectively, vs. vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3108484&req=5

Figure 5: Contractile activity following oral dosing of TD-8954 (0.01 and 0.03 mg/kg; n = 5; left-hand columns), tegaserod (0.1 and 0.3 mg/kg; n = 6; right-hand columns), and vehicles (n = 5 or 6) in the canine antrum, duodenum, and jejunum. Data are expressed as the mean (±SEM) cumulative contractile AUC in 10-min periods for 3 h post-dosing (at 0 min). Data are analyzed using a two-way analysis of variance with a Bonferroni post hoc test (*,#p < 0.05 for the 0.01, 0.03, and 0.3 mg/kg treatment groups, respectively, vs. vehicle.

Mentions: The quiescent phase of the antrum, duodenum, and jejunum motility cycle generally lasted for 50–60 min before transitioning into the pre-burst period (muscle contractions of gradually increasing magnitude occurring at random, with a duration of 30–60 min), followed by the burst period (vigorous and frequent contractions, with a duration of 5–15 min). Following oral administration of vehicle (1 mL/kg), there was little or no change in the activity of the antrum, duodenum, or jejunum; the expected motility patterns characteristic of fasted beagles were maintained throughout the observation period (Figures 5 and 6). TD-8954 (0.01 and 0.03 mg/kg) and tegaserod (0.1 and 0.3 mg/kg) produced increases in contractility in the antrum, duodenum, and jejunum (Figure 5). The onset of contractile activity with TD-8954 occurred typically within 10 min of dosing (Figure 6). Comparison of the activities of TD-8954 and tegaserod indicated that TD-8954 was statistically significantly more potent than tegaserod in the antrum, duodenum, and jejunum following oral administration (p < 0.05, ANOVA, followed by Dunnett’s post hoc test).


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)

Contractile activity following oral dosing of TD-8954 (0.01 and 0.03 mg/kg; n = 5; left-hand columns), tegaserod (0.1 and 0.3 mg/kg; n = 6; right-hand columns), and vehicles (n = 5 or 6) in the canine antrum, duodenum, and jejunum. Data are expressed as the mean (±SEM) cumulative contractile AUC in 10-min periods for 3 h post-dosing (at 0 min). Data are analyzed using a two-way analysis of variance with a Bonferroni post hoc test (*,#p < 0.05 for the 0.01, 0.03, and 0.3 mg/kg treatment groups, respectively, vs. vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Contractile activity following oral dosing of TD-8954 (0.01 and 0.03 mg/kg; n = 5; left-hand columns), tegaserod (0.1 and 0.3 mg/kg; n = 6; right-hand columns), and vehicles (n = 5 or 6) in the canine antrum, duodenum, and jejunum. Data are expressed as the mean (±SEM) cumulative contractile AUC in 10-min periods for 3 h post-dosing (at 0 min). Data are analyzed using a two-way analysis of variance with a Bonferroni post hoc test (*,#p < 0.05 for the 0.01, 0.03, and 0.3 mg/kg treatment groups, respectively, vs. vehicle.
Mentions: The quiescent phase of the antrum, duodenum, and jejunum motility cycle generally lasted for 50–60 min before transitioning into the pre-burst period (muscle contractions of gradually increasing magnitude occurring at random, with a duration of 30–60 min), followed by the burst period (vigorous and frequent contractions, with a duration of 5–15 min). Following oral administration of vehicle (1 mL/kg), there was little or no change in the activity of the antrum, duodenum, or jejunum; the expected motility patterns characteristic of fasted beagles were maintained throughout the observation period (Figures 5 and 6). TD-8954 (0.01 and 0.03 mg/kg) and tegaserod (0.1 and 0.3 mg/kg) produced increases in contractility in the antrum, duodenum, and jejunum (Figure 5). The onset of contractile activity with TD-8954 occurred typically within 10 min of dosing (Figure 6). Comparison of the activities of TD-8954 and tegaserod indicated that TD-8954 was statistically significantly more potent than tegaserod in the antrum, duodenum, and jejunum following oral administration (p < 0.05, ANOVA, followed by Dunnett’s post hoc test).

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