title: The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site.
abstract: The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.
authors.affiliation: Sandoz Pharma Limited, Basel, Switzerland.
authors.forename: K H
authors.initials: KH
authors.lastname: Buchheit
authors.forename: R
authors.initials: R
authors.lastname: Gamse
authors.forename: R
authors.initials: R
authors.lastname: Giger
authors.forename: D
authors.initials: D
authors.lastname: Hoyer
authors.forename: F
authors.initials: F
authors.lastname: Klein
authors.forename: E
authors.initials: E
authors.lastname: Klöppner
authors.forename: H J
authors.initials: HJ
authors.lastname: Pfannkuche
authors.forename: H
authors.initials: H
authors.lastname: Mattes
mesh_terms: D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008968:Molecular Conformation; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists