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

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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 (K i = 0.11–1.50 nM). Moreover, a ligand that contains a hydrogen atom attached to the basic nitrogen (R = H; K i=150 nM) is used as a control for structure–affinity relationships.

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Authors and Affiliations

  1. Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040, Madrid, Spain

    María L. López-Rodríguez, Bellinda Benhamú, Marta Murcia & Elsa Álvaro

  2. Laboratori de Medicina Computacional, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Spain

    Mercedes Campillo & Leonardo Pardo

Authors
  1. María L. López-Rodríguez
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  2. Bellinda Benhamú
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  3. Marta Murcia
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  4. Elsa Álvaro
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  5. Mercedes Campillo
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  6. Leonardo Pardo
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López-Rodríguez, M.L., Benhamú, B., Murcia, M. et al. Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists. J Comput Aided Mol Des 17, 515–524 (2003). https://doi.org/10.1023/B:JCAM.0000004601.34056.c1

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