1. 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.
- Author
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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, and Kusakabe KI
- Subjects
- Animals, Humans, Structure-Activity Relationship, Male, Drug Inverse Agonism, ERG1 Potassium Channel metabolism, ERG1 Potassium Channel antagonists & inhibitors, Rats, Mice, Piperidines pharmacology, Piperidines therapeutic use, Piperidines chemistry, Rats, Sprague-Dawley, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels metabolism, Urea analogs & derivatives, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Antipsychotic Agents chemistry, Antipsychotic Agents chemical synthesis, Receptor, Serotonin, 5-HT2A metabolism, Psychotic Disorders drug therapy, Serotonin 5-HT2 Receptor Agonists pharmacology, Serotonin 5-HT2 Receptor Agonists therapeutic use, Serotonin 5-HT2 Receptor Agonists chemistry, Receptor, Serotonin, 5-HT2C metabolism, Dementia drug therapy
- Abstract
Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin ( 1 ), a 5-HT
2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 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-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.- Published
- 2024
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