Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Grant C. Glatfelter*, Allison A. Clark, Natalie G. Cavalco, Antonio Landavazo, John S. Partilla, Marilyn Naeem, James A. Golen, Andrew R. Chadeayne, David R. Manke, Bruce E. Blough, John D. McCorvy and Michael H. Baumann, 
{"title":"Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice","authors":"Grant C. Glatfelter*,&nbsp;Allison A. Clark,&nbsp;Natalie G. Cavalco,&nbsp;Antonio Landavazo,&nbsp;John S. Partilla,&nbsp;Marilyn Naeem,&nbsp;James A. Golen,&nbsp;Andrew R. Chadeayne,&nbsp;David R. Manke,&nbsp;Bruce E. Blough,&nbsp;John D. McCorvy and Michael H. Baumann,&nbsp;","doi":"10.1021/acschemneuro.4c0051310.1021/acschemneuro.4c00513","DOIUrl":null,"url":null,"abstract":"<p >5-methoxy-<i>N</i>,<i>N</i>-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its <i>N</i>-alkyl, <i>N</i>-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT<sub>2A</sub>) and 1A receptors (5-HT<sub>1A</sub>), and 3) to examine the influence of 5-HT<sub>1A</sub> on 5-HT<sub>2A</sub>-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT<sub>2A</sub> and 5-HT<sub>1A</sub>. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED<sub>50</sub> range = 0.2–1.8 mg/kg) and maximal effects (<i>E</i><sub>max</sub> range = 20–60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED<sub>50</sub> range = 3.2–20.6 mg/kg). 5-HT<sub>2A</sub> antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT<sub>1A</sub> antagonist pretreatment enhanced HTRs. In general, <i>N</i>,<i>N</i>-dialkyl and <i>N</i>-isopropyl derivatives displayed HTR activity, while the <i>N</i>-methyl, <i>N</i>-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT<sub>1A</sub> unmasked latent HTR activity for the <i>N</i>-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40–90 HTRs/30 min), supporting the notion that 5-HT<sub>1A</sub> agonist activity can dampen 5-HT<sub>2A</sub>-mediated HTRs. Suppression of 5-HT<sub>2A</sub>-mediated HTRs by 5-HT<sub>1A</sub> only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure–activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT<sub>1A</sub> agonism in modulating acute psychoactive effects of 5-HT<sub>2A</sub> agonists.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4458–4477 4458–4477"},"PeriodicalIF":4.1000,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acschemneuro.4c00513","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

5-methoxy-N,N-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its N-alkyl, N-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT2A) and 1A receptors (5-HT1A), and 3) to examine the influence of 5-HT1A on 5-HT2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT2A and 5-HT1A. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED50 range = 0.2–1.8 mg/kg) and maximal effects (Emax range = 20–60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED50 range = 3.2–20.6 mg/kg). 5-HT2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT1A antagonist pretreatment enhanced HTRs. In general, N,N-dialkyl and N-isopropyl derivatives displayed HTR activity, while the N-methyl, N-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT1A unmasked latent HTR activity for the N-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40–90 HTRs/30 min), supporting the notion that 5-HT1A agonist activity can dampen 5-HT2A-mediated HTRs. Suppression of 5-HT2A-mediated HTRs by 5-HT1A only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure–activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT1A agonism in modulating acute psychoactive effects of 5-HT2A agonists.

Abstract Image

5-羟色胺1A受体调节5-甲氧基- n, n -二甲基色胺类似物介导的小鼠行为效应
5-甲氧基- n, n -二甲基三胺(5-MeO-DMT)类似物被用作娱乐性药物,但它们也被开发为潜在药物,需要对其药理学进行进一步研究。在这里,我们研究了5-MeO-DMT及其几种n -烷基、n -烯丙基和2-甲基类似物的神经药理学,主要有三个目的:1)确定这些化合物的体外受体谱,2)表征5-羟色胺(5-HT) 2A受体(5-HT2A)和1A受体(5-HT1A)的体外功能活性,以及3)在小鼠头抽搐反应(HTR)模型中检测5-HT1A对5-HT2A介导的致幻作用的影响。体外受体结合和功能分析表明,所有5-MeO-DMT类似物都具有高亲和力结合并激活多个靶点(例如5-HT受体亚型,α肾上腺素能受体),包括5-HT2A和5-HT1A的强效作用。在C57Bl/6J小鼠中,皮下注射类似物可诱导不同剂量(ED50范围= 0.2-1.8 mg/kg)和最大效应(Emax范围= 20-60 HTRs/30 min)的高温反应,而高剂量(ED50范围= 3.2-20.6 mg/kg)可诱导低温和低运动。5-HT2A拮抗剂预处理可阻断药物诱导的htr,而5-HT1A拮抗剂预处理可增强htr。一般来说,N、N-二烷基和N-异丙基衍生物表现出HTR活性,而N-甲基、N-乙基和2-甲基类似物则没有。重要的是,阻断5-HT1A揭示了n -乙基类似物的潜在HTR活性,并显著增加了其他HTR活性化合物的最大反应(40-90 HTR /30分钟),支持了5-HT1A激动剂活性可以抑制5- ht2a介导的HTR的观点。5-HT1A对5- ht2a介导的hts的抑制仅发生在高剂量的5-MeO-DMT后,这表明其他受体参与了迷幻样效应的调节。总的来说,我们的研究结果提供了5-MeO-DMT类似物的受体靶谱、诱导致幻作用的结构-活性关系以及5-HT1A激动剂在调节5-HT2A激动剂急性精神活性作用中的关键作用的关键信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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