Department of Chemistry, School of Science, The University of Jordan, Amman 11942, Jordan.
Department of Pharmacology, University of the Basque Country UPV/EHU, 48940 Leioa, Bizkaia, Spain.
J Med Chem. 2023 Jul 13;66(13):9057-9075. doi: 10.1021/acs.jmedchem.3c00662. Epub 2023 Jun 28.
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 (, , and ). In vitro competition receptor binding and functional G protein coupling assays demonstrated that compounds , , and 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.
人们担心第二代抗精神病药在帕金森病精神病（PDP）和与痴呆相关的精神病中的使用会产生重要的不良反应。Pimavanserin 是唯一获准用于 PDP 的抗精神病药物，它是 5-HT 受体（5-HT2AR）的反向激动剂，对多巴胺受体没有亲和力。因此，开发没有多巴胺能活性的 5-HT2AR 反向激动剂对不同的神经精神疾病是一个挑战。我们使用基于配体的药物设计，发现了 pimavanserin 类似物（、和）的新型结构。体外竞争受体结合和功能性 G 蛋白偶联测定表明，化合物、和在人皮质和重组细胞中作为 5-HT2AR 反向激动剂的效力均高于 pimavanserin。为了评估分子取代基对 5-HT2AR 选择性和反向激动作用的影响，进行了分子对接和计算机预测的物理化学参数。对接研究与体外筛选结果一致，结果与 pimavanserin 相似。
