8ZMG

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

This is a non-PDB format compatible entry.

Summary for 8ZMG

• Entry DOI: 10.2210/pdb8zmg/pdb
• Descriptor: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, Pimavanserin (2 entities in total)
• Functional Keywords: class a g protein-coupled receptor, inverse agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 94067.70

Authors

Oguma, T.,Asada, H.,Sekiguchi, Y.,Imono, M.,Iwata, S.,Kusakabe, K. (deposition date: 2024-05-23, release date: 2024-08-28, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.4 Å)