The in vitro pharmacological profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity

  title={The in vitro pharmacological profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity},
  author={J. A. M. Smith and David T. Beattie and Daniel G. Marquess and Jeng Pyng Shaw and Ross G. Vickery and Patrick P. A. Humphrey},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT4 receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT4 receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT4(c) (h5-HT4(c)) receptor (pEC50 = 8.3) and 5-HT4 receptor-mediated relaxation of the rat esophagus (pEC50 = 7.9) and contraction of the guinea pig colon (pEC50 = 7.9). In all in… 

The Pharmacology of TD-8954, a Potent and Selective 5-HT4 Receptor Agonist with Gastrointestinal Prokinetic Properties

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 and may have clinical utility in patients with disorders of reduced GI motility.

The in vitro pharmacology and non‐clinical cardiovascular safety studies of a novel 5‐HT4 receptor agonist, DSP‐6952

Translating 5-HT 4 receptor pharmacology

Pruca- lopride has now achieved the profile of good selectivity of action and high intrinsic activity at intestinal 5-HT4 receptors, without clinically-meaningful actions on 5- HT4 receptors in the heart.

5-Hydroxytryptamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 482].

Translating 5‐HT4 receptor pharmacology

  • G. Sanger
  • Biology
    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
  • 2009
The progress of this compound for treatment of chronic constipation, as well as competitor molecules such as ATI‐7505 and TD‐5108, will now be followed with interest as each attempts to differentiate themselves from each other.

Constipation, IBs and the 5-HT4 Receptor: What Role for Prucalopride?

Prucalopride is now the first of a new class of drug defined by selectivity and high intrinsic activity at the 5-HT4 receptor, characterized by good selectivity at the5-HT 4 receptor, high intrinsicactivity and efficacy in patients with chronic constipation.



The in vivo gastrointestinal activity of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity

The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal

The 5‐HT4 receptor agonist, tegaserod, is a potent 5‐HT2B receptor antagonist in vitro and in vivo

The data from this study indicate that tegaserod antagonizes 5‐ HT2B receptors at concentrations similar to those that activate 5‐HT4 receptors.

Characterization of human 5‐HT4(d) receptor desensitization in CHO cells

It is demonstrated that the C‐terminal tail of h5‐HT4 receptors may influence the rate of agonist‐induced desensitization and there is evidence for a major role of PKA in h5-HT4(d) receptor desensItization.

Effects of mosapride citrate, a 5-HT4 receptor agonist, on colonic motility in conscious guinea pigs.

It is suggested that mosapride enhances colonic motility through the 5-HT(4)-receptor activation in guinea pigs and may be useful for treating constipation in patients with colonic Motility dysfunction.

Differential functional effects of two 5-HT4 receptor isoforms in adult cardiomyocytes.

Isolation of the serotoninergic 5‐HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6‐glial and CHO cell lines

The data show that the h5‐HT4(e) receptor has a pharmacological profile which is close to the native h5-HT4 receptor in human atrium with a functional potency which is dependent on the cellular context in which the receptor is expressed.

Unaltered agonist potency upon inducible 5-HT7(a) but not 5-HT4(b) receptor expression indicates agonist-independent association of 5-HT7(a) receptor and Gs.

Interestingly, the potency of 5-HT to stimulate AC increased with increasing receptor density only in clones expressing 5- HT4(b) receptors, which supports the existence of a complex between inactive receptor and G protein, as predicted by the cubic ternary complex model.

Differential Effects of 5-Hydroxytryptamine4 Receptor Agonists at Gastric versus Cardiac Receptors: An Operational Framework to Explain and Quantify Organ-Specific Behavior

In vitro studies of gastric and cardiac effects of 5-HT4 receptor ligands in the pig indicate that these interactions do not follow a simple competitive pattern and that they differ between stomach and left atrium.

Pharmacological characterization of 5‐HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle

5‐HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5‐HT4 receptors and for the first time, a non‐human species was shown to exhibit relaxant 5‐ HT4 receptors in the large intestine.

Identification of putative 5-HT4 receptors in guinea-pig ascending colon.