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 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.
authors.affiliation: Departamento de Química Orgánica 1, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain. mluzlr@quim.ucm.es
authors.forename: Maria L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Marta
authors.initials: M
authors.lastname: Murcia
authors.forename: Elsa
authors.initials: E
authors.lastname: Alvaro
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017124:Conserved Sequence; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016011:Normal Distribution; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4