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Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.

Authors
  • Brindisi, Margherita
  • Butini, Stefania
  • Franceschini, Silvia
  • Brogi, Simone
  • Trotta, Francesco
  • Ros, Sindu
  • Cagnotto, Alfredo
  • Salmona, Mario
  • Casagni, Alice
  • Andreassi, Marco
  • Saponara, Simona
  • Gorelli, Beatrice
  • Weikop, Pia
  • Mikkelsen, Jens D
  • Scheel-Kruger, Jorgen
  • Sandager-Nielsen, Karin
  • Novellino, Ettore
  • Campiani, Giuseppe
  • Gemma, Sandra
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Nov 26, 2014
Volume
57
Issue
22
Pages
9578–9597
Identifiers
DOI: 10.1021/jm501119j
PMID: 25343529
Source
Medline
License
Unknown

Abstract

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.

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