TY - JOUR
T1 - Benzimidazole derivatives.4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists
AU - López-Rodríguez, María L.
AU - Benhamú, Bellinda
AU - Murcia, Marta
AU - Álvaro, Elsa
AU - Campillo, Mercedes
AU - Pardo, Leonardo
PY - 2003/8/1
Y1 - 2003/8/1
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.
AB - 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.
KW - 5-HT receptor 4
KW - Antagonist binding
KW - Benzimidazole derivatives
KW - Drug design
KW - G protein-coupled receptors
KW - Molecular modeling
U2 - https://doi.org/10.1023/B:JCAM.0000004601.34056.c1
DO - https://doi.org/10.1023/B:JCAM.0000004601.34056.c1
M3 - Article
VL - 17
SP - 515
EP - 524
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
SN - 0920-654X
ER -