PMID- 15466450
OWN - NLM
STAT- MEDLINE
DCOM- 20050428
LR  - 20181113
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 143
IP  - 5
DP  - 2004 Nov
TI  - The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in 
      vitro and in vivo.
PG  - 549-60
AB  - 1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist 
      with clinical efficacy in disorders associated with reduced gastrointestinal 
      motility and transit. The present study investigated the interaction of tegaserod 
      with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 
      receptor agonist activity. 2 Tegaserod had significant binding affinity for human 
      recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, 
      respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to 
      that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic 
      kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 
      Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated 
      stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist 
      activity. Tegaserod produced, with similar potency, an elevation of adenosine 
      3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 
      5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated 
      relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the 
      guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous 
      administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the 
      stomach fundus in anaesthetized rats in response to intravenous dosing of 
      alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 
      5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) 
      subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in 
      conscious guinea-pigs. 5 The data from this study indicate that tegaserod 
      antagonizes 5-HT2B receptors at concentrations similar to those that activate 
      5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor 
      antagonist activity of tegaserod contributes to its clinical profile.
FAU - Beattie, D T
AU  - Beattie DT
AD  - Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA. 
      dbeattie@theravance.com
FAU - Smith, J A M
AU  - Smith JA
FAU - Marquess, D
AU  - Marquess D
FAU - Vickery, R G
AU  - Vickery RG
FAU - Armstrong, S R
AU  - Armstrong SR
FAU - Pulido-Rios, T
AU  - Pulido-Rios T
FAU - McCullough, J L
AU  - McCullough JL
FAU - Sandlund, C
AU  - Sandlund C
FAU - Richardson, C
AU  - Richardson C
FAU - Mai, N
AU  - Mai N
FAU - Humphrey, P P A
AU  - Humphrey PP
LA  - eng
PT  - Journal Article
DEP - 20041004
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Indoles)
RN  - 0 (Receptor, Serotonin, 5-HT2B)
RN  - 0 (Serotonin Antagonists)
RN  - 0 (Serotonin Receptor Agonists)
RN  - 158165-40-3 (Receptors, Serotonin, 5-HT4)
RN  - 458VC51857 (tegaserod)
RN  - E0399OZS9N (Cyclic AMP)
SB  - IM
MH  - Animals
MH  - Cell Membrane/drug effects/metabolism
MH  - Cells, Cultured
MH  - Colon/drug effects
MH  - Cyclic AMP/metabolism
MH  - Esophagus/drug effects
MH  - Gastric Fundus/drug effects
MH  - Gastrointestinal Transit/drug effects
MH  - Guinea Pigs
MH  - In Vitro Techniques
MH  - Indoles/*pharmacology
MH  - Male
MH  - Muscle Contraction/drug effects
MH  - Muscle, Smooth/drug effects
MH  - Pressure
MH  - Protein Binding
MH  - Radioligand Assay
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, Serotonin, 5-HT2B/*drug effects
MH  - Receptors, Serotonin, 5-HT4/*drug effects
MH  - Serotonin Antagonists/*pharmacology
MH  - Serotonin Receptor Agonists/*pharmacology
PMC - PMC1575425
EDAT- 2004/10/07 09:00
MHDA- 2005/04/29 09:00
PMCR- 2005/11/01
CRDT- 2004/10/07 09:00
PHST- 2004/10/07 09:00 [pubmed]
PHST- 2005/04/29 09:00 [medline]
PHST- 2004/10/07 09:00 [entrez]
PHST- 2005/11/01 00:00 [pmc-release]
AID - sj.bjp.0705929 [pii]
AID - 10.1038/sj.bjp.0705929 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2004 Nov;143(5):549-60. doi: 10.1038/sj.bjp.0705929. Epub 2004 
      Oct 4.