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

Publication date: Jun 28, 2023

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-HT 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.

Concepts Keywords
Agonism Agonists
Drug Analogues
Ht2ars Based
Neuropsychiatric Design
Recombinant Docking


Type Source Name
drug DRUGBANK Pimavanserin
drug DRUGBANK Serotonin
disease MESH psychosis
disease MESH dementia
pathway REACTOME Dopamine receptors

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