1. Dual 5-HT2Aand 5-HT2CReceptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis
- Author
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Oguma, Takuya, Jino, Kohei, Nakahara, Kenji, Asada, Hidetsugu, Fuchino, Kouki, Nagatani, Kotaro, Kouki, Kensuke, Okamoto, Ryuji, Takai, Nozomi, Koda, Ken, Fujita, Sayaka, Sekiguchi, Yusuke, Yasuo, Kazuya, Mayumi, Kei, Abe, Ayane, Imono, Masaaki, Horiguchi, Naotaka, Iwata, So, and Kusakabe, Ken-ichi
- Abstract
Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson’s disease psychosis, pimavanserin (1), a 5-HT2Areceptor inverse agonist having minimal 5-HT2Creceptor affinity and no dopamine D2receptor 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-HT2Aand 5-HT2Creceptor inverse agonist 8having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2Aand 5-HT2Creceptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2Aand 5-HT2Coccupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2Caffinity in 1followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8that showed significant antipsychotic efficacy due to the involvement of both receptors.
- Published
- 2024
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