Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York.
Int J Neuropsychopharmacol. 2018 Sep 1;21(9):847-857. doi: 10.1093/ijnp/pyy034.
The kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA).
BPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin.
BPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination.
BPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.
κ 阿片受体系统已被揭示为治疗物质滥用成瘾的潜在药物治疗靶点。κ 阿片受体激动剂已被证明可阻断精神兴奋剂的奖赏和多巴胺释放作用。最近的研究对偏向 G 蛋白介导信号转导的化合物的体内效应进行了分析，这些化合物的信号转导能力较弱。这里研究的化合物源自一系列三烷基胺：取代的 N-苯乙基-N-3-羟基苯乙基-胺，取代基包括正丁基（BPHA）、甲基环丁基（MCBPHA）和甲基环戊基（MCPPHA）。
在表达 κ 阿片受体的细胞系中，通过结合测定和功能测定对 BPHA、MCBPHA 和 MCPPHA 进行了表征。我们还在 C57BL6 小鼠中测试了这些化合物，通过旋转棒测试评估共济失调，以及检测神经内分泌 κ 阿片受体生物标志物催乳素的循环水平。
与参比化合物 U69,593 相比，BPHA、MCBPHA 和 MCPPHA 对 G 蛋白偶联显示出完全的 κ 阿片受体激动作用。BPHA 未显示出可测量的β-arrestin-2 募集，表明其非常偏向 G 蛋白。然而，MCBPHA 和 MCPPHA 对β-arrestin-2 的募集显示出亚最大功效。在 C57BL6 小鼠中的研究表明，所有化合物均刺激催乳素的释放，这与对 G 蛋白信号的依赖性一致。MCBPHA 和 MCPPHA 导致旋转棒共济失调，而 BPHA 则不会，这与报道的 κ 阿片受体/β-arrestin-2 介导的偶联对于 κ 阿片受体激动剂诱导的旋转棒共济失调所必需的一致。
因此，BPHA、MCBPHA 和 MCPPHA 是新型的、不同程度偏向 G 蛋白的 κ 阿片受体激动剂。它们可用于研究信号通路如何介导体外和体内 κ 阿片受体效应，并探索候选 κ 阿片受体靶向药物治疗的效果。
