Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator.

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-27 DOI:10.1016/j.jpet.2025.103401
Blaise M Costa, De'Yana Hines, Nakia Phillip, Seth C Boehringer, Ramu Anandakrishnan, McAlister Council-Troche, Jennifer L Davis
{"title":"Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator.","authors":"Blaise M Costa, De'Yana Hines, Nakia Phillip, Seth C Boehringer, Ramu Anandakrishnan, McAlister Council-Troche, Jennifer L Davis","doi":"10.1016/j.jpet.2025.103401","DOIUrl":null,"url":null,"abstract":"<p><p>N-methyl D-aspartate receptor (NMDAR) channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated the in vivo effects of costa NMDAR stimulator 4 (CNS4), a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours after intraperitoneal injection, with brain concentrations reaching values up to 8.4% of those in plasma (64.9 vs 5.47 μg/mL). Preliminary results showed that CNS4, a nonopioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared with saline. In a fear conditioning experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs 1; females, 19 vs 3). CNS4 also improved hyperarousal behavior (25 vs 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after fear conditioning training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects such as those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel nonopioid analgesic, warranting further investigation. SIGNIFICANCE STATEMENT: N-methyl D-aspartate (NMDA)-subtype glutamate receptors are an attractive target for chronic pain and posttraumatic stress disorder treatments because they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, costa NMDA receptor stimulator 4.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103401"},"PeriodicalIF":3.1000,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pharmacology and Experimental Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jpet.2025.103401","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

N-methyl D-aspartate receptor (NMDAR) channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated the in vivo effects of costa NMDAR stimulator 4 (CNS4), a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours after intraperitoneal injection, with brain concentrations reaching values up to 8.4% of those in plasma (64.9 vs 5.47 μg/mL). Preliminary results showed that CNS4, a nonopioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared with saline. In a fear conditioning experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs 1; females, 19 vs 3). CNS4 also improved hyperarousal behavior (25 vs 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after fear conditioning training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects such as those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel nonopioid analgesic, warranting further investigation. SIGNIFICANCE STATEMENT: N-methyl D-aspartate (NMDA)-subtype glutamate receptors are an attractive target for chronic pain and posttraumatic stress disorder treatments because they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, costa NMDA receptor stimulator 4.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
期刊最新文献
Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator. Metabolomic and lipidomic profiling reveals convergent pathways in attention deficit hyperactivity disorder therapeutics: Insights from established and emerging treatments. γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice. Predicting the effects of single pathological mutations in hemophilia A and type 2N von Willebrand diseases using AlphaFold2-multimer and AlphaFold3. Managing thrombus formation with EL2-5HTVac: A selective vaccination-based approach targeting the platelet serotonin 5-HT2AR.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1