SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats

IF 3.5 3区医学 Q2 NEUROSCIENCES

Frontiers in Molecular Neuroscience Pub Date : 2024-09-05 DOI:10.3389/fnmol.2024.1459098

Kevin M. Braunscheidel, George Voren, Christie D. Fowler, Qun Lu, Alexander Kuryatov, Michael D. Cameron, Ines Ibañez-Tallon, Jon M. Lindstrom, Theodore M. Kamenecka, Paul J. Kenny

{"title":"SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats","authors":"Kevin M. Braunscheidel, George Voren, Christie D. Fowler, Qun Lu, Alexander Kuryatov, Michael D. Cameron, Ines Ibañez-Tallon, Jon M. Lindstrom, Theodore M. Kamenecka, Paul J. Kenny","doi":"10.3389/fnmol.2024.1459098","DOIUrl":null,"url":null,"abstract":"Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents. 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) enhances the activity of α4β2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of α4/α4 and α4/α5 subunits. The NS9283 derivative 3-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)benzonitrile (SR9883) similarly enhanced the effect of nicotine on α4β2* nAChR stoichiometries that contain low-affinity agonist binding sites, with EC50 values ranging from 0.2–0.4 μM. SR9883 had no effect on any stoichiometry of α3β2* and α3β4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg−1) and oral (10–20 mg kg−1) administration and penetrated into the brain. When administered alone, SR9883 (5–10 mg kg−1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg−1) decreased responding for intravenous nicotine infusions (0.03 mg kg−1 per infusion) but had no effect on responding for food rewards in rats. Together, these data suggest that SR9883 is useful for investigating physiological and behavioral processes regulated by certain stoichiometries α4β2* nAChRs, including the motivational properties of nicotine. SR9883 or related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Molecular Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fnmol.2024.1459098","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents. 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) enhances the activity of α4β2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of α4/α4 and α4/α5 subunits. The NS9283 derivative 3-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)benzonitrile (SR9883) similarly enhanced the effect of nicotine on α4β2* nAChR stoichiometries that contain low-affinity agonist binding sites, with EC50 values ranging from 0.2–0.4 μM. SR9883 had no effect on any stoichiometry of α3β2* and α3β4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg−1) and oral (10–20 mg kg−1) administration and penetrated into the brain. When administered alone, SR9883 (5–10 mg kg−1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg−1) decreased responding for intravenous nicotine infusions (0.03 mg kg−1 per infusion) but had no effect on responding for food rewards in rats. Together, these data suggest that SR9883 is useful for investigating physiological and behavioral processes regulated by certain stoichiometries α4β2* nAChRs, including the motivational properties of nicotine. SR9883 or related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.

查看原文本刊更多论文

SR9883 是一种新型小分子α4β2* 尼古丁乙酰胆碱受体信号增强剂，可降低大鼠的尼古丁静脉自我给药

即使使用目前最有效的戒烟药物治疗，大多数试图戒烟的吸烟者也会很快复吸。这凸显了开发有效戒烟新药的必要性。有证据表明，正性异位调节剂（PAM）和其他尼古丁乙酰胆碱受体（nAChR）信号转导增强剂可作为戒烟药物发挥治疗作用。3-[3-(3-吡啶基)-1,2,4-恶二唑-5-基]苯腈（NS9283）可增强α4β2* nAChR stoichiometries 的活性，该 stoichiometries 在 α4/α4 和 α4/α5 亚基的界面处含有一个低亲和力激动剂结合位点。NS9283 衍生物 3-(5-(吡啶-3-基)-2H-四唑-2-基)苯腈（SR9883）同样增强了尼古丁对含有低亲和力激动剂结合位点的α4β2* nAChR结构单元的作用，EC50 值为 0.2-0.4 μM。SR9883 对 α3β2* 和 α3β4* nAChRs 的任何结构均无影响。SR9883 在静脉注射（1 毫克/公斤-1）和口服（10-20 毫克/公斤-1）后均可生物利用，并可渗透至大脑。单独给药时，SR9883（5-10 毫克/千克）对小鼠的运动活动或颅内自我刺激（ICSS）阈值没有影响。当与尼古丁同时给药时，SR9883 会增强尼古丁诱导的运动抑制和 ICSS 阈值的升高。SR9883（5 毫克和 10 毫克/公斤-1）可降低大鼠对静脉注射尼古丁（每次 0.03 毫克/公斤-1）的反应，但对大鼠对食物奖励的反应没有影响。总之，这些数据表明 SR9883 有助于研究受某些化学计量 α4β2* nAChRs 调节的生理和行为过程，包括尼古丁的激励特性。SR9883 或相关化合物具有良好的类药物理化和药理特性，有望成为烟草使用障碍的新型治疗方法。

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

Frontiers in Molecular Neuroscience NEUROSCIENCES-

CiteScore

5.70

自引率

2.10%

发文量

669

审稿时长

14 weeks

期刊介绍： Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.

文献相关原料

公司名称	产品信息	采购帮参考价格