title: 5-HT3 receptor antagonists. 3. Quinoline derivatives which may be effective in the therapy of irritable bowel syndrome.
abstract: A series of quinolinecarboxylic acid derivatives has been previously described as a new class of 5-HT3 receptor antagonists due to deviation of a carbonyl moiety from the place of an aromatic ring in their minimum-energy conformations. These derivatives were evaluated in a wrap-restraint 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 derivatives exhibited different activities depending on structural class. 4-Hydroxyquinoline-3-carboxylic acid derivatives 5 and 6a possess high affinity for the 5-HT3 receptor (Ki = 6.1 and 1.5 nM, respectively) and exhibit potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.0017 and 0.000 10 mg/kg, i.v., respectively), but they did not effectively 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 than 1 or 2 but inhibited restraint stress-induced defecation more potently than 1 or 2. The ID50 value of endo-8-methyl-8- azabicyclo[3.2.1]oct-3-yl 1-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 of 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 reported 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, 10e exhibited activity as potent as 4 in 5-HT- and TRH-induced defecation assays; 10e exhibited 7-fold increased potency compared with 4 in wrap-restraint stress-induced colonic propulsions. From these results, 10e appears to interact selectively with 5-HT3 receptors in the gastrointestinal system and might be effective in the therapy of irritable bowel syndrome (IBS).
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Miwa
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: S
authors.initials: S
authors.lastname: Ichikawa
authors.forename: H
authors.initials: H
authors.lastname: Nonaka
authors.forename: T
authors.initials: T
authors.lastname: Yokoyama
authors.forename: F
authors.initials: F
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology; D002368:Castor Oil / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003109:Colonic Diseases, Functional / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005772:Gastrointestinal Transit / Q000187:drug effects; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D013312:Stress, Physiological / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
chemical_list: D002264:Carboxylic Acids; D005765:Gastrointestinal Agents; D011804:Quinolines; D012702:Serotonin Antagonists; D012701:Serotonin; D013973:Thyrotropin-Releasing Hormone; D002368:Castor Oil