title: New benzimidazole derivatives: selective and orally active 5-HT3 receptor antagonists.
abstract: The synthesis of new 5-HT(3) receptor antagonists is an interesting field of research because of their wide therapeutic use. The aim of this work is to functionally characterise a new series of benzimidazole derivatives previously described. These compounds bind to 5-HT(3) receptors and have been evaluated using in vitro (rat tunica muscularis mucosae) and in vivo tests (Bezold-Jarisch reflex in rat and gastrointestinal motility and spontaneous motility in mice). Ondansetron and 1-[4-amino-5-chloro-2-(3,5-dimethoxyphenil)methyloxy]-3-[1-[2-methylsulfonylamino]piperidin-4-yl]propan-1-one hydrochloride (RS 39604) were used as well known 5-HT(3) and 5-HT(4) receptor antagonists. These benzimidazole derivatives have proved to be 5-HT(3) receptor antagonists. Interestingly, they are as active as ondansetron when they are intraperitoneally (i.p.) or orally (p.o.) administered and, in mice, they seem to induce fewer behavioural changes at similar effective doses than does ondansetron. The present results confirm the usefulness of the previously proposed pharmacophore and justify the interest in these new benzimidazole derivatives.
authors.affiliation: Unidad de Farmacología, Departamento Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922, Alcorcón, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pascual
authors.forename: Rocío
authors.initials: R
authors.lastname: Girón
authors.forename: Angela
authors.initials: A
authors.lastname: Alsasua
authors.forename: Belinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: María Luz
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Martín
mesh_terms: D006916:5-Hydroxytryptophan / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D017294:Ondansetron / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D001372:Aza Compounds; D001562:Benzimidazoles; C475120:N-(1-azabicicle(2.2.2)oct-3-yl)-6-chloro-7-nitrobenzimidazole-4-carboxamide; C475119:N-(1-azabicicle(2.2.2)oct-3-yl)-6-chlorobenzimidazole-4-carboxamide; C475118:N-(1-azabicicle(2.2.2)oct-3-yl)benzimidazole-4-carboxamide; D010880:Piperidines; C475107:RS 39604; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D012701:Serotonin; D017294:Ondansetron; D002217:Carbachol; D006916:5-Hydroxytryptophan; C031000:benzimidazole; D011407:Propane