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

  • J Med Chem. 2009 Jan 8;52(1):151-69. doi: 10.1021/jm800689g.
Stefania Butini  1 ,  Sandra Gemma ,  Giuseppe Campiani ,  Silvia Franceschini ,  Francesco Trotta ,  Marianna Borriello ,  Nicoletta Ceres ,  Sindu Ros ,  Salvatore Sanna Coccone ,  Matteo Bernetti ,  Meri De Angelis ,  Margherita Brindisi ,  Vito Nacci ,  Isabella Fiorini ,  Ettore Novellino ,  Alfredo Cagnotto ,  Tiziana Mennini ,  Karin Sandager-Nielsen ,  Jesper Tobias Andreasen ,  Jorgen Scheel-Kruger ,  Jens D Mikkelsen ,  Caterina Fattorusso
Affiliations
  • 1. European Research Centre for Drug Discovery and Development, University of Siena, Siena, Italy.
PMID: 19072656 DOI: 10.1021/jm800689g
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.

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