Design, Synthesis, Molecular Docking, and Biological Evaluation of Novel Pimavanserin-Based Analogues as Potential Serotonin 5-HT2A Receptor Inverse Agonists

  • J Med Chem. 2023 Jun 28. doi: 10.1021/acs.jmedchem.3c00662.
Nader R Albujuq  1 ,  J Javier Meana  2  3  4 ,  Rebeca Diez-Alarcia  2  3  4 ,  Itziar Muneta-Arrate  2  3 ,  Arshi Naqvi  5 ,  Khalid Althumayri  5 ,  Mosa Alsehli  5
Affiliations
  • 1. Department of Chemistry, School of Science, The University of Jordan, Amman 11942, Jordan.
  • 2. Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain.
  • 3. Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, 48940 Leioa, Bizkaia, Spain.
  • 4. Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Bizkaia, Spain.
  • 5. Chemistry Department, College of Science, Taibah University, Al Madinah, Al Munwarah 30002, Saudi Arabia.
PMID: 37378639 DOI: 10.1021/acs.jmedchem.3c00662
Abstract

There is concern for important adverse effects with use of second-generation antipsychotics in Parkinson's disease psychosis (PDP) and dementia-related psychosis. Pimavanserin is the only antipsychotic drug authorized for PDP and represents an inverse agonist of 5-HT2A receptors (5-HT2AR) lacking affinity for dopamine receptors. Therefore, the development of serotonin 5-HT2AR inverse agonists without dopaminergic activity represents a challenge for different neuropsychiatric disorders. Using ligand-based drug design, we discovered a novel structure of pimavanserin analogues (2, 3, and 4). In vitro competition receptor binding and functional G protein coupling assays demonstrated that compounds 2, 3, and 4 showed higher potency than pimavanserin as 5-HT2AR inverse agonists in the human brain cortex and recombinant cells. To assess the effect of molecular substituents for selectivity and inverse agonism at 5-HT2ARs, molecular docking and in silico predicted physicochemical parameters were performed. Docking studies were in agreement with in vitro screenings and the results resembled pimavanserin.

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