title: Novel antagonists of serotonin-4 receptors: synthesis and biological evaluation of pyrrolothienopyrazines.
abstract: Based on the definition of a 5-HT(4) receptor antagonist pharmacophore, a series of pyrrolo[1,2-a]thieno[3,2-e] and pyrrolo[1,2-a]thieno[2,3-e] pyrazine derivatives were designed, prepared, and evaluated to determine the properties necessary for high-affinity binding to 5-HT(4) receptors. The compounds were synthesized by substituting the chlorine atom of the pyrazine ring with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR113808 (1) as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) were affected by both the substituent on the aromatic ring and the substituent on the lateral piperidine chain. A methyl group on the tricyclic ring produced a marked increase in affinity while an N-propyl or N-butyl group gave compounds with nanomolar affinities. Among the most potent ligands, 34d was selected for further pharmacological studies and evaluated in vivo. This compound acts as an antagonist/weak partial agonist in COS-7 cells stably expressing the 5-HT(4(a)) receptor and is of great interest as a peripheral antinociceptive agent.
authors.affiliation: Centre d'Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, 1 rue Vaubénard, 14032 Caen Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lemaître
authors.forename: Alban
authors.initials: A
authors.lastname: Lepailleur
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.forename: Sabrina
authors.initials: S
authors.lastname: Butt-Gueulle
authors.forename: Véronique
authors.initials: V
authors.lastname: Lelong-Boulouard
authors.forename: Pascal
authors.initials: P
authors.lastname: Duchatelle
authors.forename: Michel
authors.initials: M
authors.lastname: Boulouard
authors.forename: Aline
authors.initials: A
authors.lastname: Dumuis
authors.forename: Cyril
authors.initials: C
authors.lastname: Daveu
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: François
authors.initials: F
authors.lastname: Dauphin
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000378:metabolism
chemical_list: D007211:Indoles; D011719:Pyrazines; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists; D013449:Sulfonamides; C082871:GR 113808