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.
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.
Butini
Stefania
S
European Research Centre for Drug Discovery and Development, University of Siena, Siena, Italy.
Gemma
Sandra
S
Campiani
Giuseppe
G
Franceschini
Silvia
S
Trotta
Francesco
F
Borriello
Marianna
M
Ceres
Nicoletta
N
Ros
Sindu
S
Coccone
Salvatore Sanna
SS
Bernetti
Matteo
M
De Angelis
Meri
M
Brindisi
Margherita
M
Nacci
Vito
V
Fiorini
Isabella
I
Novellino
Ettore
E
Cagnotto
Alfredo
A
Mennini
Tiziana
T
Sandager-Nielsen
Karin
K
Andreasen
Jesper Tobias
JT
Scheel-Kruger
Jorgen
J
Mikkelsen
Jens D
JD
Fattorusso
Caterina
C
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
D014150:Antipsychotic Agents; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D050637:Receptors, Dopamine D3; D044282:Receptor, Serotonin, 5-HT1A