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

• Published in: Journal of medicinal chemistry Vol. 66; no. 13; pp. 9057 - 9075
• Main Authors: Albujuq, Nader R., Meana, J. Javier, Diez-Alarcia, Rebeca, Muneta-Arrate, Itziar, Naqvi, Arshi, Althumayri, Khalid, Alsehli, Mosa
• Format: Journal Article
• Language: English
• Published: American Chemical Society 13-07-2023
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00662

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.