title: Pharmacological properties of a novel class of 5-HT3 receptor antagonists.
abstract: The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.
authors.affiliation: Istituto De Angeli, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Turconi
authors.forename: A
authors.initials: A
authors.lastname: Donetti
authors.forename: A
authors.initials: A
authors.lastname: Schiavone
authors.forename: A
authors.initials: A
authors.lastname: Sagrada
authors.forename: E
authors.initials: E
authors.lastname: Montagna
authors.forename: M
authors.initials: M
authors.lastname: Nicola
authors.forename: R
authors.initials: R
authors.lastname: Cesana
authors.forename: C
authors.initials: C
authors.lastname: Rizzi
authors.forename: R
authors.initials: R
authors.lastname: Micheletti
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002945:Cisplatin / Q000009:adverse effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D013270:Stomach / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D001562:Benzimidazoles; D012702:Serotonin Antagonists; D012701:Serotonin; D002945:Cisplatin