Inhibition of colonic motility and defecation by RS-127445 suggests an involvement of the 5-HT2B receptor in rodent large bowel physiology

Background: 5-HT2B 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-HT2B receptor antagonist RS-127445 and studied its effects on peristalsis and defecation. Experimental approach: Although reported as a selective 5-HT2B receptor antagonist, any interactions of RS-127445 with 5-HT4 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. Key results: RS-127445 (up to 1 mu mol.L-1) did not interact with the 5-HT4 receptor. RS-127445 (0.001-1 mmol.L-1) did not affect EFS-induced contractions of the colon, although at 10 mmol.L-1 the contractions were reduced (to 36 + 8% of control, n = 4). RS-127445 (0.1-10 mmol.L-1) concentration-dependently reduced peristaltic frequency (n = 4). RS-127445 (1-30 mg.kg(-1)), dose-dependently reduced faecal output, reaching significance at 10 and 30 mg.kg(-1) (n = 6-11). In blood and brain, >98% of RS-127445 was protein-bound. Conclusions and implications: High-protein binding of RS-127445 indicates that relatively high doses are required for efficacy. The results suggest that 5-HT2B receptors tonically regulate colonic motility. British Journal of Pharmacology (2009) 158, 252-258; doi:10.1111/j.1476-5381.2009.00155.x; published online 9 April 2009