BENZOXAZOLE DERIVATIVES AS NOVEL 5-HT3 RECEPTOR PARTIAL AGONISTS IN THE GUT

A series of benzoxazoles with a nitrogen-containing heterocyclic subst ituent at the 2-position was prepared and evaluated for 5-HT3 partial agonist activity on isolated guinea pig ileum. The nature of the subst ituent at the 5-position of the benzoxazole ring affected the potency for the 5-HT3 receptor, and the 5-chloro derivatives showed increased potency and lowered intrinsic activity. 7-methyl-2-(4-methyl-1-homopip erazinyl)benzoxazole (6v) exhibited a high binding affinity in the sam e range as that of the 5-HT3 antagonist granisetron, and its intrinsic activity was 12% of that of 5-HT. Compound 6v inhibited 5-HT-evoked d iarrhea but did not prolong the transition time of glass beads in the normal distal colon even at a dose of 100 times the ED50 for diarrhea inhibition in mice. Compounds of this type are expected to be effectiv e for the treatment of irritable bowel syndrome without the side effec t of constipation.