Inhibition of colonic motility and defecation by RS-127445 suggests an involvement of the 5-HT2B receptor in rodent large bowel physiology.
BACKGROUND
5-HT(2B) receptors are localized within the myenteric nervous system, but their functions on motor/sensory neurons are unclear. To explore the role of these receptors, we further characterized the 5-HT(2B) receptor antagonist RS-127445 and studied its effects on peristalsis and defecation.


METHODS
Although reported as a selective 5-HT(2B) receptor antagonist, any interactions of RS-127445 with 5-HT(4) receptors are unknown; this was examined using the recombinant receptor and Biomolecular Interaction Detection technology. Mouse isolated colon was mounted in tissue baths for isometric recording of neuronal contractions evoked by electrical field stimulation (EFS), or under an intraluminal pressure gradient to induce peristalsis; the effects of RS-127445 on EFS-induced and on peristaltic contractions were measured. Faecal output of rats in grid-bottom cages was measured over 3 h following i.p. RS-127445 and separately, validation of the effective doses was achieved by determining the free, unbound fraction of RS-127445 in blood and brain.


RESULTS
RS-127445 (up to 1 micromol x L(-1)) did not interact with the 5-HT(4) receptor. RS-127445 (0.001-1 micromol x L(-1)) did not affect EFS-induced contractions of the colon, although at 10 micromol x L(-1) the contractions were reduced (to 36 +/- 8% of control, n= 4). RS-127445 (0.1-10 micromol x L(-1)) concentration-dependently reduced peristaltic frequency (n= 4). RS-127445 (1-30 mg x kg(-1)), dose-dependently reduced faecal output, reaching significance at 10 and 30 mg x kg(-1) (n= 6-11). In blood and brain, >98% of RS-127445 was protein-bound.


CONCLUSIONS
High-protein binding of RS-127445 indicates that relatively high doses are required for efficacy. The results suggest that 5-HT(2B) receptors tonically regulate colonic motility.
Bassil
A K
AK
Immuno-Inflammation CEDD, GlaxoSmithKline, Stevenage, UK.
Taylor
C M
CM
Bolton
V J N
VJ
Gray
K M
KM
Brown
J D
JD
Cutler
L
L
Summerfield
S G
SG
Bruton
G
G
Winchester
W J
WJ
Lee
K
K
Sanger
G J
GJ
D000818:Animals; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D003672:Defecation / Q000187:drug effects / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007420:Intestine, Large / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists
D011743:Pyrimidines; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine