Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model.
Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model.
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DOI：
10.1021/acschemneuro.2c00779
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发表时间：
2023-03-01
影响因子：
5
通讯作者：
Liotta, Dennis C.
中科院分区：
文献类型：
--
作者：
Harris, Lynnea D.;Regan, Michael C.;Myers, Scott J.;Nocilla, Kelsey A.;Akins, Nicholas S.;Tahirovic, Yesim A.;Wilson, Lawrence J.;Dingledine, Ray;Furukawa, Hiro;Traynelis, Stephen F.;Liotta, Dennis C.
许多与药物过量相关的意外死亡病例是由于长期使用阿片类药物，耐受性和成瘾。镇痛耐受的特征在于对阿片类药物的镇痛作用的反应降低，需要越来越高的剂量来维持所需的疼痛缓解水平。含有GluN 2B的N-甲基-d-天冬氨酸受体的过度活化被认为在镇痛耐受性发展中发生的细胞适应的基础机制中起关键作用。在此，我们描述了一种新的GluN 2B选择性负变构调节剂，EU 93 -108，它显示出高效力和脑转移。我们描述了在原子分辨率结合的结构基础。该化合物在啮齿动物尾部浸泡试验中具有内在镇痛特性。EU 93 -108具有急性和显著的止痛作用，由此与单独的吗啡相比，吗啡与EU 93 -108组合时产生更高的甩尾潜伏期。这些数据表明，GluN 2B作为靶点的参与在疼痛治疗中具有实用性，并且EU 93 -108可以作为询问该假设的适当工具化合物。未来围绕这种支架的结构-活性关系工作可能会产生可以与阿片类药物共同给药的化合物，以减少由于长期使用阿片类药物而导致的耐受性发作，从而改变其效用。
Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to maintain the desired level of pain relief. Overactivation of GluN2B-containing N-methyl-d-Aspartate receptors is thought to play a key role in mechanisms underlying cellular adaptation that takes place in the development of analgesic tolerance. Herein, we describe a novel GluN2B-selective negative allosteric modulator, EU93-108, that shows high potency and brain penetrance. We describe the structural basis for binding at atomic resolution. This compound possesses intrinsic analgesic properties in the rodent tail immersion test. EU93-108 has an acute and significant anodyne effect, whereby morphine when combined with EU93-108 produces a higher tail flick latency compared to that of morphine alone. These data suggest that engagement of GluN2B as a target has utility in the treatment of pain, and EU93-108 could serve as an appropriate tool compound to interrogate this hypothesis. Future structure–activity relationship work around this scaffold could give rise to compounds that can be co-administered with opioids to diminish the onset of tolerance due to chronic opioid use, thereby modifying their utility.
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影响因子：
16.8
作者：
Chou, Tsung-Han;Epstein, Max;Michalski, Kevin;Fine, Eve;Biggin, Philip C.;Furukawa, Hiro
通讯作者：
Furukawa, Hiro
影响因子：
10.6
作者：
aan het Rot, Marije;Collins, Katherine A.;Mathew, Sanjay J.
通讯作者：
Mathew, Sanjay J.
影响因子：
6.6
作者：
Coyle, Joseph T.
通讯作者：
Coyle, Joseph T.
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
3.4
作者：
Cook, CD;Barrett, AC;Picker, MJ
通讯作者：
Picker, MJ