Linked Life Data

10425096

Source:http://linkedlifedata.com/resource/pubmed/id/10425096

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
1999-8-31
pubmed:abstractText
A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide derivatives bearing a piperazine moiety was synthesized. Their in vitro 5-HT(4), 5-HT(3), and D(2) receptors affinities were evaluated by radioligand binding assay. For selected compounds functional studies at the 5-HT(4) receptor were made by using precontracted (by carbachol) preparations of rat esophageal tunica muscularis mucosae (TMM). The influence of the 3-substituent of the benzimidazole ring, the 4-substituent of the piperazine moiety, and the alkylene spacer was studied. Compounds with an ethyl or a cyclopropyl substituent in the 3-position of the benzimidazole ring showed moderate to high affinity (K(i) = 6.7-75.4 nM) for the 5-HT(4) receptor with selectivity over 5-HT(3) and D(2) receptors and moderate antagonist activity (pK(b) = 6.19-7.73). Compounds with an isopropyl substituent in the 3-benzimidazole position exhibited moderate and selective 5-HT(4) affinity (K(i) >/= 38.9 nM) and a partial agonist activity (5a, i.a. = 0.94) higher than that of the reference compound BIMU 8 (i.a. = 0.70). This reversal of the pharmacological activity due only to a small structural difference might confirm the existence of two binding sites on the 5-HT(4) receptor. In the alkylene spacer, a two-methylene chain is favorable to optimize the affinity and the antagonist or the partial agonist activity. In the ethyl and cyclopropyl series, 5-HT(4) antagonist activity seems to be unrelated to the size of the 4-substituent of the piperazine moiety, whereas a methyl group is optimal for high partial agonist activity in the isopropyl series; however, the presence of a butyl substituent is a favorable pattern for 5-HT(4) antagonism and even causes a reversal of the pharmacological profile in the isopropyl series (5h, pK(b) = 7.94). N-Butyl quaternization of 5a led to an improvement in affinity for the 5-HT(4) receptor and mantained the high partial agonist activity (5r, K(i) = 66.3 nM, i.a. = 0.93).
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2870-80
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:10425096-Amides, pubmed-meshheading:10425096-Animals, pubmed-meshheading:10425096-Benzimidazoles, pubmed-meshheading:10425096-Corpus Striatum, pubmed-meshheading:10425096-Entorhinal Cortex, pubmed-meshheading:10425096-Esophagus, pubmed-meshheading:10425096-Guinea Pigs, pubmed-meshheading:10425096-Male, pubmed-meshheading:10425096-Muscle, Smooth, pubmed-meshheading:10425096-Radioligand Assay, pubmed-meshheading:10425096-Rats, pubmed-meshheading:10425096-Rats, Wistar, pubmed-meshheading:10425096-Receptors, Dopamine D2, pubmed-meshheading:10425096-Receptors, Serotonin, pubmed-meshheading:10425096-Receptors, Serotonin, 5-HT3, pubmed-meshheading:10425096-Receptors, Serotonin, 5-HT4, pubmed-meshheading:10425096-Serotonin Antagonists, pubmed-meshheading:10425096-Serotonin Receptor Agonists, pubmed-meshheading:10425096-Structure-Activity Relationship
pubmed:year
1999
pubmed:articleTitle
2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxamides with selective affinity for the 5-HT(4) receptor: synthesis and structure-affinity and structure-activity relationships of a new series of partial agonist and antagonist derivatives.
pubmed:affiliation
Departamento de Investigación, FAES, S.A., Máximo Aguirre 14, 48940 Leioa, Vizcaya, Spain.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't