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

María L. López-Rodríguez, Bellinda Benhamú, Marta Murcia, Elsa Álvaro, Mercedes Campillo, Leonardo Pardo

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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 I 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.

Original languageEnglish (US)
Pages (from-to)515-524
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Volume17
Issue number8
DOIs
StatePublished - Aug 1 2003

Keywords

  • 5-HT receptor
  • Antagonist binding
  • Benzimidazole derivatives
  • Drug design
  • G protein-coupled receptors
  • Molecular modeling

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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