K. Itoh et al., Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor, EUR J MED C, 34(12), 1999, pp. 1101-1108
A series of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethy
l)benzamides was synthesized as novel gastroprokinetic agents. The affinity
of these compounds for the 5-hydroxytryptamine 4 (5-HT4) receptor was eval
uated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methyli
ndol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959)
showed a higher affinity for the 5-HT4 receptor (Ki = 0.30 nmol/L) than for
other receptors, and was confirmed to be a potent 5-HT4 receptor agonist h
aving contractile effects in the isolated guinea-pig ascending colon (EC50
= 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of
both the gastric antrum and the ascending colon. In addition, this effect o
n the colon was inhibited by azasetron, a selective 5-HT3 receptor antagoni
st, demonstrating that the effect of gastroprokinetic agents having 5-HT3 r
eceptor antagonism on the colon were reduced compared with that of selectiv
e 5-HT4 receptor agonists. (C) 1999 Editions scientifiques et medicales Els
evier SAS.