Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 378, Issue 1, pp 125–137

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

  • J. A. M. Smith
  • D. T. Beattie
  • D. Marquess
  • J.-P. Shaw
  • R. G. Vickery
  • P. P. A. Humphrey
Short Communication

DOI: 10.1007/s00210-008-0282-y

Cite this article as:
Smith, J.A.M., Beattie, D.T., Marquess, D. et al. Naunyn-Schmied Arch Pharmacol (2008) 378: 125. doi:10.1007/s00210-008-0282-y

Abstract

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 vitro assays, TD-5108 was a high intrinsic activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower intrinsic activity. TD-5108 had high affinity (pKi = 7.7) and selectivity (≥25-fold) for h5-HT4(c) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT2B and h5-HT3A) and, at 3 μM, had no effect on human ether-à-go-go-related gene K+ channels. In conclusion, TD-5108 is a selective 5-HT4 receptor agonist in vitro. The high intrinsic activity and preferential binding of TD-5108 to 5-HT4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.

Keywords

GastrointestinalSerotonin5-HT4TD-5108Tegaserod

Abbreviations

DMEM

Dulbecco’s Modified Eagles Medium

HEK-293

Human embryonic kidney 293

IBS

Irritable bowel syndrome

LMMP

longitudinal muscle/myenteric plexus

SMP

Submucous plexus

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • J. A. M. Smith
    • 1
  • D. T. Beattie
    • 1
  • D. Marquess
    • 1
  • J.-P. Shaw
    • 1
  • R. G. Vickery
    • 1
  • P. P. A. Humphrey
    • 1
  1. 1.Theravance, Inc.South San FranciscoUSA