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

doi:10.1023/B:JCAM.0000004601.34056.c1

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

Academic Engagement

Research output: Contribution to journal › Article › peer-review

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 (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.

Original language	English (US)
Pages (from-to)	515-524
Number of pages	10
Journal	Journal of Computer-Aided Molecular Design
Volume	17
Issue number	8
DOIs	https://doi.org/10.1023/B:JCAM.0000004601.34056.c1
State	Published - Aug 2003

Funding

This work has been supported by the Ministerio de Ciencia y Tecnología (BQU2001-1459; SAF2003-02730), and the Universidad Complutense (PR486/97-7483). Some of the simulations were run at the Centre de Computació i Comunicacions de Catalunya. The authors are grateful to Universidad Complutense for a predoctoral grant to M. Murcia and to Comunidad de Madrid for a technician grant to E. Álvaro.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1023/B:JCAM.0000004601.34056.c1

Cite this

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

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.",

keywords = "5-HT receptor, Antagonist binding, Benzimidazole derivatives, Drug design, G protein-coupled receptors, Molecular modeling",

author = "L{\'o}pez-Rodr{\'i}guez, \{Mar{\'i}a L.\} and Bellinda Benham{\'u} and Marta Murcia and Elsa {\'A}lvaro and Mercedes Campillo and Leonardo Pardo",

note = "Funding Information: This work has been supported by the Ministerio de Ciencia y Tecnolog{\'i}a (BQU2001-1459; SAF2003-02730), and the Universidad Complutense (PR486/97-7483). Some of the simulations were run at the Centre de Computaci{\'o} i Comunicacions de Catalunya. The authors are grateful to Universidad Complutense for a predoctoral grant to M. Murcia and to Comunidad de Madrid for a technician grant to E. {\'A}lvaro.",

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AU - Benhamú, Bellinda

AU - Murcia, Marta

AU - Álvaro, Elsa

AU - Campillo, Mercedes

AU - Pardo, Leonardo

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N2 - 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.

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