Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists

We report a structure-affinity analysis of an important element in the pharmacophore model for the recognition of 5-HT4 receptor antagonists: the voluminous substituent attached to the basic nitrogen of the ligand. We have designed, synthesized and pharmacologically evaluated a series of benzimidazo...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 2003-08, Vol.17 (8), p.515-524
Main Authors: López-Rodríguez, Maria L, Benhamú, Bellinda, Murcia, Marta, Alvaro, Elsa, Campillo, Mercedes, Pardo, Leonardo
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Conserved Sequence
Drug Design
Enzymes
Male
Models, Molecular
Molecular Sequence Data
Normal Distribution
Protein Conformation
Rats
Rats, Sprague-Dawley
Receptors, Serotonin, 5-HT4 - chemistry
Receptors, Serotonin, 5-HT4 - drug effects
Receptors, Serotonin, 5-HT4 - physiology
Serotonin 5-HT4 Receptor Antagonists
Serotonin Antagonists - chemical synthesis
Serotonin Antagonists - chemistry
Serotonin Antagonists - pharmacology
Structure-Activity Relationship
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Summary:We report a structure-affinity analysis of an important element in the pharmacophore model for the recognition of 5-HT4 receptor antagonists: the voluminous substituent attached to the basic nitrogen of the ligand. We have designed, synthesized and pharmacologically evaluated a series of benzimidazole derivatives 1 containing a common molecular skeleton formed by N-[(4-piperidyl)methyl]-6-chlorobenzimidazole-4-carboxamide and four different substituents (R = butyl, 2-[(methylsulfonyl)amino]ethyl, 5-[(phenylacetyl)amino]pentyl, and 5-[(benzylsulfonyl)amino]pentyl). These compounds possess binding affinities in the nM range (Ki = 0.11-1.50 nM). Moreover, a ligand that contains a hydrogen atom attached to the basic nitrogen (R = H; Ki = 150 nM) is used as a control for structure-affinity relationships.
ISSN:0920-654X
1573-4951
DOI:10.1023/B:JCAM.0000004601.34056.c1