TY - JOUR
T1 - Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors for Developing Effective Antipsychotics
T2 - Synthesis, Biological Characterization, and Behavioral Studies
AU - Brindisi, Margherita
AU - Butini, Stefania
AU - Franceschini, Silvia
AU - Brogi, Simone
AU - Trotta, Francesco
AU - Ros, Sindu
AU - Cagnotto, Alfredo
AU - Salmona, Mario
AU - Casagni, Alice
AU - Andreassi, Marco
AU - Saponara, Simona
AU - Gorelli, Beatrice
AU - Weikop, Pia
AU - Mikkelsen, Jens D.
AU - Scheel-Kruger, Jorgen
AU - Sandager-Nielsen, Karin
AU - Novellino, Ettore
AU - Campiani, Giuseppe
AU - Gemma, Sandra
PY - 2014/11/26
Y1 - 2014/11/26
N2 - Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.
AB - Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.
KW - Amides
KW - Animals
KW - Antipsychotic Agents
KW - Behavior, Animal
KW - Dizocilpine Maleate
KW - Dopamine Antagonists
KW - Drug Evaluation, Preclinical
KW - Female
KW - Kinetics
KW - Ligands
KW - Male
KW - Mice
KW - Prefrontal Cortex
KW - Protein Binding
KW - Rats
KW - Rats, Sprague-Dawley
KW - Receptor, Serotonin, 5-HT1A
KW - Receptor, Serotonin, 5-HT2A
KW - Receptors, Dopamine D3
KW - Schizophrenia
KW - Serotonin Receptor Agonists
KW - Structure-Activity Relationship
U2 - 10.1021/jm501119j
DO - 10.1021/jm501119j
M3 - Journal article
C2 - 25343529
SN - 0022-2623
VL - 57
SP - 9578
EP - 9597
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -