A comparison of the pharmacological properties of guinea-pig and human recombinant 5-HT4 receptors.

Full Abstract

BACKGROUND

AND PURPOSE:
5-HT(4) receptor agonists are used therapeutically to treat disorders of reduced gastrointestinal motility. Since such compounds are evaluated in guinea-pigs, we cloned, expressed and pharmacologically characterized the guinea-pig 5-HT(4) and human 5-HT(4(b)) splice variant, which share 95% homology. The functional properties of guinea-pig 5-HT(4(b)) receptors were compared with native receptors in guinea-pig colon.

EXPERIMENTAL APPROACH:
Membrane radioligand binding and whole cell cAMP accumulation assays were used to determine the affinities, potencies and intrinsic activities (IA). Contraction of the guinea-pig distal colon longitudinal muscle myenteric plexus preparation (LMMP) was monitored to evaluate functional activity.

KEY RESULTS:
pK(i) values for guinea-pig and human recombinant receptors, and guinea-pig striatum 5-HT(4) receptors, were in agreement, as were the potency and IA values for guinea-pig and human 5-HT(4) receptors expressed at a similar density ( approximately 0.2 pmol mg(-1) protein). Tegaserod was a potent (pEC(50)=8.4 and 8.7, respectively), full agonist at both guinea-pig and human 5-HT(4) receptors. In contrast, in the LMMP preparation, tegaserod was a potent, partial agonist (pEC(50)=8.2; IA=66%).

CONCLUSIONS AND IMPLICATIONS:
Close agreement between the pharmacological properties of guinea-pig and human 5-HT(4) receptors support the use of guinea-pig model systems for the identification of 5-HT(4) receptor therapeutics. However, the mechanisms underlying the different agonist properties of tegaserod in recombinant and isolated tissue preparations, and the extent to which these impact the clinical efficacy of tegaserod as a prokinetic agent, remain to be determined.

Learn Faster Today Improve your study skills

Author information

Author/s: Vickery, R G (RG); Mai, N (N); Kaufman, E (E); Beattie, D T (DT); Pulido-Rios, T (T); O'Keefe, M (M); Humphrey, P P A (PP); Smith, J A M (JA);

Affiliation: Department of Molecular and Cell Biology, Theravance Inc., South San Francisco, CA 94080, USA. rvickery(-atsign-)(-atsign-)theravance.com

Journal and publication information

Publication Type: Comparative Study; In Vitro; Journal Article

Journal: British journal of pharmacology (Br J Pharmacol), published in England. (Language: eng)

Reference: 2007-Mar; vol 150 (issue 6) : pp 782-91

Dates: Created 2007/03/19; Completed 2007/05/03; Revised 2008/11/20;

PMID: 17293885, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article (including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.

MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alternative Splicing
Animals
Base Sequence
Colon - drug effects; metabolism
DNA Primers - genetics
Digestive System - drug effects; metabolism
Gastrointestinal Agents - pharmacology
Guinea Pigs

Guinea Pigs
Humans
Indoles - pharmacology
Male
RNA, Messenger - genetics; metabolism
Receptors, Serotonin, 5-HT4 - agonists; genetics; metabolism
Recombinant Proteins - agonists; genetics; metabolism
Serotonin Agonists - pharmacology

Associated Chemicals: DNA Primers (0) ; Gastrointestinal Agents (0) ; Indoles (0) ; RNA, Messenger (0) ; Recombinant Proteins (0) ; Serotonin Agonists (0) ; tegaserod (145158-71-0) ; Receptors, Serotonin, 5-HT4 (158165-40-3)

These are the highest related articles currently in the database:

See 100+ related articles.