title: Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.
abstract: Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
authors.affiliation: European Research Centre for Drug Discovery and Development, University of Siena, Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschini
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
authors.forename: Marianna
authors.initials: M
authors.lastname: Borriello
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ceres
authors.forename: Sindu
authors.initials: S
authors.lastname: Ros
authors.forename: Salvatore Sanna
authors.initials: SS
authors.lastname: Coccone
authors.forename: Matteo
authors.initials: M
authors.lastname: Bernetti
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Karin
authors.initials: K
authors.lastname: Sandager-Nielsen
authors.forename: Jesper Tobias
authors.initials: JT
authors.lastname: Andreasen
authors.forename: Jorgen
authors.initials: J
authors.lastname: Scheel-Kruger
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D050637:Receptors, Dopamine D3; D044282:Receptor, Serotonin, 5-HT1A