5-HT(3) RECEPTOR ANTAGONISTS .3. QUINOLINE DERIVATIVES WHICH MAY BE EFFECTIVE IN THE THERAPY OF IRRITABLE-BOWEL-SYNDROME

A series of quinolinecarboxylic acid derivatives has been previously d escribed as a new class of 5-HT3 receptor antagonists due to deviation of a carbonyl moiety from the plane of an aromatic ring in their mini mum-energy conformations. These derivatives were evaluated in a wrap-r estraint stress-induced defecation model in rats. Reference compounds, ondansetron (1), granisetron (2), and YM060 (4), potently inhibited a stress-induced increase in stools excreted from fed rats (ID50 = 0.27 , 0.12, and 0.0052 mg/kg, po, respectively). However, quinoline deriva tives exhibited different activities depending on structural class. 4- Hydroxyquinoline-3-carboxylic acid derivatives 5 and 6a possess high a ffinity for the 5-HT3 receptor (K(i) = 6.1 and 1.5 nM, respectively) a nd exhibit potent activity in the Bezold-Jarisch (B-J) reflex test (ED 50 = 0.0017 and 0.000 10 mg/kg, iv, respectively), but they did not ef fectively inhibit the increase in fecal pellet output at the dose of 1 mg/kg, po. On the other hand, most of 1-substituted 2-oxoquinoline-4- carboxylates 10 showed less potent activity in the B-J reflex test tha n 1 or 2 but inhibited restraint stress-induced defecation more potent ly than 1 or 2. The ID50 value of endo-8-methyl-8-azabicyclo[3.2.1]oct -3-yl -isobutyl-2-oxo-1,2-dihydro-4-quinolinecarboxylate 10e was 0.013 mg/kg, po. With respect to the selected compounds 6a and 10e, effects on 5-HT- and thyrotropin-releasing hormone (TRH)-induced defecation, castor oil-induced diarrhea and wrap-restraint stress-induced colonic propulsion in rats were examined. These 5-HT3 receptor antagonists did not effectively inhibit castor oil-induced diarrhea, which has been r eported not to be mediated via the 5-HT3 receptor. Although 10e showed 800-fold decreased potency compared with 4 in the B-J reflex test, 10 e exhibited activity as potent as 4 in 5-HT- and TRH-induced defecatio n assays; 10e exhibited 7-fold increased potency compared with 4 in wr ap-restraint stress-induced colonic propulsions. From these results, 1 0e appears to interact selectively with 5-HT3 receptors in the gastroi ntestinal system and might be effective in the therapy of irritable bo wel syndrome (IBS).