Kai Zhang1,2, Hidetoh Toki3, Yuko Fujita1, Min Ma1, Lijia Chang1, Youge Qu1, Shingo Harada4, Tetsuhiro Nemoto4, Akiko Mizuno-Yasuhira3, Jun-Ichi Yamaguchi3, Shigeyuki Chaki3, Kenji Hashimoto5. 1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. 2. Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China. 3. Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. 4. Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. 5. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
Abstract
RATIONALE: (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. METHODS: We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model. RESULTS: Pharmacokinetic studies showed that levels of (2R,6R)-d1-hydroxynorketamine [(2R,6R)-d1-HNK], a final metabolite of (R)-d2-ketamine, in the plasma and brain after administration of (R)-d2-ketamine (10 mg/kg) were lower than those of (2R,6R)-HNK from (R)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2R,6R)-HNK. In contrast, levels of (R)-ketamine and its metabolite (R)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (R)-ketamine (10 mg/kg) and (R)-d2-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (R)-ketamine. CONCLUSIONS: The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (R)-ketamine to (2R,6R)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (R)-ketamine in a CSDS model. Therefore, it is unlikely that (2R,6R)-HNK is essential for antidepressant effects of (R)-ketamine.
RATIONALE: (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. METHODS: We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model. RESULTS: Pharmacokinetic studies showed that levels of (2R,6R)-d1-hydroxynorketamine [(2R,6R)-d1-HNK], a final metabolite of (R)-d2-ketamine, in the plasma and brain after administration of (R)-d2-ketamine (10 mg/kg) were lower than those of (2R,6R)-HNK from (R)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2R,6R)-HNK. In contrast, levels of (R)-ketamine and its metabolite (R)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (R)-ketamine (10 mg/kg) and (R)-d2-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (R)-ketamine. CONCLUSIONS: The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (R)-ketamine to (2R,6R)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (R)-ketamine in a CSDS model. Therefore, it is unlikely that (2R,6R)-HNK is essential for antidepressant effects of (R)-ketamine.
Authors: Jaclyn N Highland; Panos Zanos; Lace M Riggs; Polymnia Georgiou; Sarah M Clark; Patrick J Morris; Ruin Moaddel; Craig J Thomas; Carlos A Zarate; Edna F R Pereira; Todd D Gould Journal: Pharmacol Rev Date: 2021-04 Impact factor: 25.468
Authors: Alona V Zlatska; Roman G Vasyliev; Inna M Gordiienko; Anzhela E Rodnichenko; Maria A Morozova; Maria A Vulf; Dmytro O Zubov; Svitlana N Novikova; Larisa S Litvinova; Tatiana V Grebennikova; Igor A Zlatskiy; Anton V Syroeshkin Journal: Sci Rep Date: 2020-03-23 Impact factor: 4.379