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).

Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4-carboxylic Acid Derivatives

“…The quinoline ring occurs in various natural products and represents a key motif in medicinal chemistry [9][10][11][12], and its derivatives, quinoline-4-carboxylic acids, are a group of compounds associated with different biological activities, such asantiviral [13], anti-inflammatory [14], antimicrobial [15], anti-atherothrombosis [16], antiemetic [17], anxiolytic [18], antimalarial and antileishmanial [19]. Although quinoline-4-carboxylic acid derivatives exhibit various bioactivities, the research of new quinoline-4-carboxylic acid-based antibacterial drugs has developed slowly.…”

Altered serotonin immunoreactivities in the left colon of patients with colonic inertia

“…Serotonin (5‐hydroxytryptamine, 5‐HT) is an important neurotransmitter and paracrine acting hormone that in part mediates various enteric functions [6,7]. Recently, a number of in vivo studies have suggested that colonic transit or motility can be accelerated by serotonin agonists [8] and inhibited by serotonin antagonists [7,9–11]. These studies verified that specific serotonin receptors (mainly subtype 1p, 3 and 4), which are expressed on cells of various structures of the colonic wall, probably mediate the regulative role of serotonin or its antagonists and analogs.…”

Review article: the pathogenesis of diverticular disease - current perspectives on motility and neurotransmitters

“…Action of serotonin and its modulators on the gastrointestinal tract. In vivo studies have shown that serotonin agonists such as prucalopride (5‐HT 4 agonist) 100 accelerate colonic motility, whereas serotonin antagonists, especially on 5‐HT 3 receptors, 94, 101, 102 inhibit colonic transit or motility leading to the inference that serotonin has an excitatory effect on the gut. Serotonin selective reuptake inhibitor (SSRI), fluoxetine, which inhibits mucosal 5‐HT uptake increases activation of 5‐HT 89 .…”