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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

Concentration–response curves to TD-8954 (n = 24), tegaserod (n = 13), cisapride (n = 10), mosapride (n = 3), prucalopride (n = 24), and 5-HT (n = 26) in the guinea pig isolated colonic LMMP preparation. Values are expressed as the mean (±SEM) change in tension, as a percentage of the primed 5-HT (0.3 μM) response in the same tissue.
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Figure 2: Concentration–response curves to TD-8954 (n = 24), tegaserod (n = 13), cisapride (n = 10), mosapride (n = 3), prucalopride (n = 24), and 5-HT (n = 26) in the guinea pig isolated colonic LMMP preparation. Values are expressed as the mean (±SEM) change in tension, as a percentage of the primed 5-HT (0.3 μM) response in the same tissue.

Mentions: TD-8954, tegaserod, cisapride, prucalopride, and mosapride produced concentration-dependent contraction of the guinea pig colonic LMMP (Figure 2). Comparison of the mean pEC50 (±SEM) values for the compounds indicated a rank order of potency of TD-8954 (pEC50 = 8.6) > tegaserod (pEC50 = 7.9) = prucalopride (pEC50 = 7.7) > cisapride (pEC50 = 7.0) > mosapride (pEC50 = 5.4). TD-8954 had a mean IA (55% of the 5-HT maximum) lower than that of cisapride and prucalopride (75 and 81%, respectively), but higher than that of tegaserod (45%) and mosapride (37%; Table 1). Incubation of tissues with the selective 5-HT4 receptor antagonist, piboserod (0.3 μM), resulted in a 614-fold shift (apparent pKb value = 9.3) of the TD-8954 concentration–response curve (data not shown).


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)

Concentration–response curves to TD-8954 (n = 24), tegaserod (n = 13), cisapride (n = 10), mosapride (n = 3), prucalopride (n = 24), and 5-HT (n = 26) in the guinea pig isolated colonic LMMP preparation. Values are expressed as the mean (±SEM) change in tension, as a percentage of the primed 5-HT (0.3 μM) response in the same tissue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Concentration–response curves to TD-8954 (n = 24), tegaserod (n = 13), cisapride (n = 10), mosapride (n = 3), prucalopride (n = 24), and 5-HT (n = 26) in the guinea pig isolated colonic LMMP preparation. Values are expressed as the mean (±SEM) change in tension, as a percentage of the primed 5-HT (0.3 μM) response in the same tissue.
Mentions: TD-8954, tegaserod, cisapride, prucalopride, and mosapride produced concentration-dependent contraction of the guinea pig colonic LMMP (Figure 2). Comparison of the mean pEC50 (±SEM) values for the compounds indicated a rank order of potency of TD-8954 (pEC50 = 8.6) > tegaserod (pEC50 = 7.9) = prucalopride (pEC50 = 7.7) > cisapride (pEC50 = 7.0) > mosapride (pEC50 = 5.4). TD-8954 had a mean IA (55% of the 5-HT maximum) lower than that of cisapride and prucalopride (75 and 81%, respectively), but higher than that of tegaserod (45%) and mosapride (37%; Table 1). Incubation of tissues with the selective 5-HT4 receptor antagonist, piboserod (0.3 μM), resulted in a 614-fold shift (apparent pKb value = 9.3) of the TD-8954 concentration–response curve (data not shown).

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