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选择性可逆 FAAH 抑制剂 SSR411298 可恢复啮齿动物对急性和慢性应激的适应不良行为的发展。

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents.

机构信息

Sanofi, Strategy & Business Development, Chilly-Mazarin, France.

Sanofi R&D, Global Project Management, Immuno-Inflammation, Chilly-Mazarin, France.

出版信息

Sci Rep. 2018 Feb 5;8(1):2416. doi: 10.1038/s41598-018-20895-z.

DOI:10.1038/s41598-018-20895-z
PMID:29403000
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5799259/
Abstract

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

摘要

增强内源性大麻素 (eCB) 信号已被认为是治疗与应激相关疾病的一种潜在策略。脂肪酸酰胺水解酶 (FAAH) 是内源性大麻素大麻素 (AEA)、油酰胺乙醇酰胺 (OEA) 和棕榈酰乙醇酰胺 (PEA) 的主要降解酶。本研究描述了一种有效的可逆 FAAH 抑制剂 SSR411298。该药物作为 FAAH 的选择性抑制剂，可在小鼠中强烈增加海马体中的 AEA、OEA 和 PEA 水平。尽管 SSR411298 能提高 eCB 水平，但它不会模拟直接作用的大麻素所引起的内脏感觉状态或产生行为副作用（记忆缺陷和运动障碍）。当 SSR411298 在焦虑模型中进行测试时，它仅在经历创伤事件（如在小鼠防御测试电池和社交挫败程序中）后处于高度厌恶的条件下，才表现出明显的抗焦虑样作用。在抑郁模型中的实验结果表明，SSR411298 在大鼠强迫游泳试验和小鼠慢性轻度应激模型中产生了强烈的抗抑郁样作用，显著恢复了对慢性应激的不适当应对反应的发展。这种临床前特征使 SSR411298 成为一种有前途的候选药物，可用于治疗创伤后应激障碍等疾病，这些疾病涉及到适应性行为的发展。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bcf4/5799259/6d6be47f97b7/41598_2018_20895_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bcf4/5799259/9a5672e973ba/41598_2018_20895_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bcf4/5799259/8c9ac3f84117/41598_2018_20895_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bcf4/5799259/97556be68ce4/41598_2018_20895_Fig9_HTML.jpg
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