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Piboserod (SB 207266), a Selective 5-HT4 Receptor Antagonist, Reduces Serotonin Potentiation of Neurally-Mediated Contractile Responses of Human Detrusor Muscle

Piboserod (SB 207266), a Selective 5-HT4 Receptor Antagonist, Reduces Serotonin Potentiation of Neurally-Mediated Contractile Responses of Human Detrusor Muscle

B Darblade, D Behr-Roussel, D Gorny, T Lebret, G Benoit, J-P Hieble, D Brooks, L Alexandre, F Giuliano

World J Urol. 2005 Jun;23(2):147-51.

PMID: 15902472

Abstract:

The aim of this study is to evaluate the potency of piboserod (SB 207266), a selective 5-HT(4) receptor antagonist, at inhibiting the 5-HT(4)-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied continuously at 1 min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1 nM-100 microM) were constructed in the absence or presence of 1 or 100 nM of piboserod. The experiments were performed in the presence of methysergide (1 microM) and ondansetron (3 microM) to block 5HT(1)/5HT(2) and 5-HT(3) receptors, respectively. 5-HT potentiated the contractile responses to EFS of human bladder strips in a concentration-dependent manner, with a maximum mean of 60.0+/-19.9% of the basal EFS-evoked contractions. Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0+/-7.9 and 38.7+/-8.7%, respectively. A mean apparent antagonist dissociation constant value (K(B)) of 0.56+/-0.09 nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. Therefore, the 5-HT(4) receptor might represent an attractive pharmacological target for the treatment of overactive bladder.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP152811626	SB-207266		152811-62-6	Price

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