| Autor: |
Albujuq, Nader R., Meana, J. Javier, Diez-Alarcia, Rebeca, Muneta-Arrate, Itziar, Naqvi, Arshi, Althumayri, Khalid, Alsehli, Mosa |
| Zdroj: |
Journal of Medicinal Chemistry; July 2023, Vol. 66 Issue: 13 p9057-9075, 19p |
| Abstrakt: |
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-HT2Areceptors (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 4showed 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. |
| Databáze: |
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