8ZMG

Crystal structure of an inverse agonist antipsychotic drug pimavanserin-bound 5-HT2A

これはPDB形式変換不可エントリーです。

8ZMG の概要

• エントリーDOI: 10.2210/pdb8zmg/pdb
• 分子名称: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, Pimavanserin (2 entities in total)
• 機能のキーワード: class a g protein-coupled receptor, inverse agonist, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 94067.70

構造登録者

Oguma, T.,Asada, H.,Sekiguchi, Y.,Imono, M.,Iwata, S.,Kusakabe, K. (登録日: 2024-05-23, 公開日: 2024-08-28, 最終更新日: 2024-10-09)

主引用文献

Oguma, T.,Jino, K.,Nakahara, K.,Asada, H.,Fuchino, K.,Nagatani, K.,Kouki, K.,Okamoto, R.,Takai, N.,Koda, K.,Fujita, S.,Sekiguchi, Y.,Yasuo, K.,Mayumi, K.,Abe, A.,Imono, M.,Horiguchi, N.,Iwata, S.,Kusakabe, K.I.
Dual 5-HT 2A and 5-HT 2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.
J.Med.Chem., 67:14478-14492, 2024

PubMed Abstract: Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (), a 5-HT receptor inverse agonist having minimal 5-HT receptor affinity and no dopamine D receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT and 5-HT receptor inverse agonist having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT and 5-HT receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT and 5-HT occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT affinity in followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to that showed significant antipsychotic efficacy due to the involvement of both receptors.

PubMed: 39137033
DOI: 10.1021/acs.jmedchem.4c01244

実験手法

X-RAY DIFFRACTION (3.4 Å)