HINT1 Inhibitors as Selective Modulators of MOR-NMDAR Cross-Regulation and Non-Opioid Analgesia.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Neuroscience Pub Date : 2025-02-19 Epub Date: 2025-02-06 DOI:10.1021/acschemneuro.4c00564
Maxwell Dillenburg, Cristina D Peterson, Rafal Dolot, Kostana Ligori, Kelley F Kitto, George L Wilcox, Carolyn A Fairbanks, Carston R Wagner
{"title":"HINT1 Inhibitors as Selective Modulators of MOR-NMDAR Cross-Regulation and Non-Opioid Analgesia.","authors":"Maxwell Dillenburg, Cristina D Peterson, Rafal Dolot, Kostana Ligori, Kelley F Kitto, George L Wilcox, Carolyn A Fairbanks, Carston R Wagner","doi":"10.1021/acschemneuro.4c00564","DOIUrl":null,"url":null,"abstract":"<p><p>Human histidine triad nucleotide-binding protein 1 (HINT1) has recently become a protein of interest due to its involvement in several CNS processes, including neuroplasticity and the development of several neuropsychiatric disorders. Crucially, HINT1 behaves as a mediator for cross-regulation of the mu-opioid receptor (MOR) and <i>N</i>-methyl-d-aspartate receptor (NMDAR). Active site inhibition of HINT1 using small-molecule inhibitors has been demonstrated to have a significant impact on this cross-regulatory relationship in vivo. Herein, we describe the development of a series of ethenoadenosine HINT1 inhibitors to further evaluate the effect of HINT1 inhibition on morphine's blockade of NMDA-evoked behaviors, the development of acute endomorphin-2 tolerance, and analgesia. X-ray crystallographic analysis and HINT1 binding experiments demonstrate that modifications to the inhibitor nucleobase greatly impact the inhibitor binding interactions with HINT1. Our results reveal a complex structure-activity relationship for HINT1 inhibitors, in which minor modifications to the ethenoadenosine scaffold resulted in dramatic changes to their activity in these assays modeling MOR-NMDAR interaction. Specifically, we observed the ability of HINT1 inhibitors to selectively affect individual pathways of MOR-NMDAR crosstalk. Furthermore, we observed that a carbamate ethenoadenosine inhibitor of HINT1 can induce analgesia while not affecting opioid tolerance. Additionally, although past studies have indicated that the loss of HINT1 expression can result in the downregulation of p53, we have shown that the inhibition of HINT1 has no effect on either the expression of HINT1 or p53. These studies highlight the critical role of HINT1 in MOR-NMDAR crosstalk and demonstrate the intriguing potential of using HINT1 active-site inhibitors as tools to probe its role in these biochemical pathways and its potential as a novel pain target.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"604-618"},"PeriodicalIF":4.1000,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acschemneuro.4c00564","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/6 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Human histidine triad nucleotide-binding protein 1 (HINT1) has recently become a protein of interest due to its involvement in several CNS processes, including neuroplasticity and the development of several neuropsychiatric disorders. Crucially, HINT1 behaves as a mediator for cross-regulation of the mu-opioid receptor (MOR) and N-methyl-d-aspartate receptor (NMDAR). Active site inhibition of HINT1 using small-molecule inhibitors has been demonstrated to have a significant impact on this cross-regulatory relationship in vivo. Herein, we describe the development of a series of ethenoadenosine HINT1 inhibitors to further evaluate the effect of HINT1 inhibition on morphine's blockade of NMDA-evoked behaviors, the development of acute endomorphin-2 tolerance, and analgesia. X-ray crystallographic analysis and HINT1 binding experiments demonstrate that modifications to the inhibitor nucleobase greatly impact the inhibitor binding interactions with HINT1. Our results reveal a complex structure-activity relationship for HINT1 inhibitors, in which minor modifications to the ethenoadenosine scaffold resulted in dramatic changes to their activity in these assays modeling MOR-NMDAR interaction. Specifically, we observed the ability of HINT1 inhibitors to selectively affect individual pathways of MOR-NMDAR crosstalk. Furthermore, we observed that a carbamate ethenoadenosine inhibitor of HINT1 can induce analgesia while not affecting opioid tolerance. Additionally, although past studies have indicated that the loss of HINT1 expression can result in the downregulation of p53, we have shown that the inhibition of HINT1 has no effect on either the expression of HINT1 or p53. These studies highlight the critical role of HINT1 in MOR-NMDAR crosstalk and demonstrate the intriguing potential of using HINT1 active-site inhibitors as tools to probe its role in these biochemical pathways and its potential as a novel pain target.

求助全文
约1分钟内获得全文 求助全文
来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信