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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
22
|
| pubmed:dateCreated |
1993-12-10
|
| pubmed:abstractText |
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).
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| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Carboxylic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Castor Oil,
http://linkedlifedata.com/resource/pubmed/chemical/Gastrointestinal Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Quinolines,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Thyrotropin-Releasing Hormone
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
29
|
| pubmed:volume |
36
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3286-92
|
| pubmed:dateRevised |
2008-11-21
|
| pubmed:meshHeading |
pubmed-meshheading:8230119-Animals,
pubmed-meshheading:8230119-Carboxylic Acids,
pubmed-meshheading:8230119-Castor Oil,
pubmed-meshheading:8230119-Colon,
pubmed-meshheading:8230119-Colonic Diseases, Functional,
pubmed-meshheading:8230119-Defecation,
pubmed-meshheading:8230119-Diarrhea,
pubmed-meshheading:8230119-Disease Models, Animal,
pubmed-meshheading:8230119-Gastrointestinal Agents,
pubmed-meshheading:8230119-Gastrointestinal Transit,
pubmed-meshheading:8230119-Male,
pubmed-meshheading:8230119-Quinolines,
pubmed-meshheading:8230119-Rats,
pubmed-meshheading:8230119-Rats, Sprague-Dawley,
pubmed-meshheading:8230119-Rats, Wistar,
pubmed-meshheading:8230119-Serotonin,
pubmed-meshheading:8230119-Serotonin Antagonists,
pubmed-meshheading:8230119-Stress, Physiological,
pubmed-meshheading:8230119-Structure-Activity Relationship,
pubmed-meshheading:8230119-Thyrotropin-Releasing Hormone
|
| pubmed:year |
1993
|
| pubmed:articleTitle |
5-HT3 receptor antagonists. 3. Quinoline derivatives which may be effective in the therapy of irritable bowel syndrome.
|
| pubmed:affiliation |
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
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| pubmed:publicationType |
Journal Article
|