Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.
Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.
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DOI：
10.1111/bph.13854
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发表时间：
2017-08
影响因子：
7.3
通讯作者：
McLaughlin JP
中科院分区：
文献类型：
--
作者：
Spetea M;Eans SO;Ganno ML;Lantero A;Mairegger M;Toll L;Schmidhammer H;McLaughlin JP
κ受体在调节中枢和外周神经元回路中的神经传递中具有中心作用，所述中枢和外周神经元回路有助于疼痛和其他行为反应。尽管κ受体激动剂不产生欣快或导致呼吸抑制，但它们诱导烦躁不安和镇静。我们假设，脑渗透κ受体配体对G蛋白信号传导的激动作用优于β-arrestin 2募集，这将产生强大的抗伤害感受作用，相关责任较少。在小鼠抗伤害感受试验中，通过55°C温水缩尾试验、旋转棒中的运动活动和条件性位置偏爱，评估了两种具有高κ受体选择性的新型二苯乙胺类药物HS 665和HS 666 i. c. v.给药后。[35 S]-GTPγS结合和β-抑制蛋白2募集体外试验用于表征偏倚激动作用。HS 665（κ受体激动剂）和HS 666（κ受体部分激动剂）在κ受体介导的i. c. v.给药后表现出剂量依赖性镇痛作用。这些高选择性κ受体配体在体外显示出不同的偏向G蛋白偶联的信号传导，这与降低的倾向性特征一致，反映在HS 666的镇静作用降低和不存在条件性位置厌恶。HS 665和HS 666激活中枢κ受体以产生强效抗伤害感受，其中HS 666显示κ受体镇痛剂的药理学特征，具有与其在β-arrestin 2信号传导途径中的低功效相关的厌恶效应的可能性降低。我们的数据提供了进一步了解中枢κ受体在疼痛抑制中的作用，以及将HS 665和HS 666的抗伤害作用与κ受体介导的不良反应分离的前景。
The κ receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although κ receptor agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain‐penetrant κ receptor ligands possessing biased agonism towards G protein signalling over β‐arrestin2 recruitment would produce robust antinociception with fewer associated liabilities. Two new diphenethylamines with high κ receptor selectivity, HS665 and HS666, were assessed following i.c.v. administration in mouse assays of antinociception with the 55°C warm‐water tail withdrawal test, locomotor activity in the rotorod and conditioned place preference. The [35S]‐GTPγS binding and β‐arrestin2 recruitment in vitro assays were used to characterize biased agonism. HS665 (κ receptor agonist) and HS666 (κ receptor partial agonist) demonstrated dose‐dependent antinociception after i.c.v. administration mediated by the κ receptor. These highly selective κ receptor ligands displayed varying biased signalling towards G protein coupling in vitro, consistent with a reduced liability profile, reflected by reduced sedation and absence of conditioned place aversion for HS666. HS665 and HS666 activate central κ receptors to produce potent antinociception, with HS666 displaying pharmacological characteristics of a κ receptor analgesic with reduced liability for aversive effects correlating with its low efficacy in the β‐arrestin2 signalling pathway. Our data provide further understanding of the contribution of central κ receptors in pain suppression, and the prospect of dissociating the antinociceptive effects of HS665 and HS666 from κ receptor‐mediated adverse effects.
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影响因子：
6.1
作者：
Barber, A;Gottschlich, R
通讯作者：
Gottschlich, R
影响因子：
5.6
作者：
Cahill CM;Taylor AM;Cook C;Ong E;Morón JA;Evans CJ
通讯作者：
Evans CJ
DOI：
10.1007/978-1-4939-2914-6_12
发表时间：
2015-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Bohn, Laura M;Zhou, Lei;Ho, Jo-Hao
通讯作者：
Ho, Jo-Hao
影响因子：
3.4
作者：
Bruchas, Michael R.;Chavkin, Charles
通讯作者：
Chavkin, Charles
影响因子：
7.3
作者：
Eans, Shainnel O.;Ganno, Michelle L.;McLaughlin, Jay P.
通讯作者：
McLaughlin, Jay P.