Antidepressant-Like Effects of Intracerebroventricular Injection of Nociceptin Analogs in Mice.

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Osamu Nakagawasai, Kohei Takahashi, Futa Kuroda, Akihiro Ambo, Mayu Abe, Wataru Nemoto, Koichi Tan-No
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Abstract

Opioid receptors and their endogenous ligands are novel targets for the treatment of depression. The nociception (NOP) receptor is structurally similar to the opioid receptor, but NOP is known to have a low affinity for the opioid receptor subtypes μ, δ, and κ. In previous studies, we synthesized peptides with a high affinity for opioid receptors and investigated their antidepressant-like effects in mice. However, we have not yet examined whether NOP-related analogs have antidepressant-like effects. Herein, we synthesized NOP analogs (peptide-1-peptide-8) by solid-phase peptide synthesis using the 9-fluorenylmethyloxycarbony (Fmoc) method with Acetyl-Arg-Tyr-Tyr-Arg-Ile-Arg-NH2 (Ac-RYYRIR-NH2) as the lead compound. We examined the affinities and antagonistic activities of the analogs for the NOP receptor using receptor-binding and mouse vas deferens assays, and their effects on the duration of immobile behavior in a tail suspension test. Peptide-6 showed a high affinity and antagonistic activity for the NOP receptor. The intracerebroventricular administration of peptide-6 in mice shortened the duration of immobile behavior, whereas the co-administration of NOP inhibited this effect. Moreover, intracerebroventricular administration of the selective NOP receptor antagonist J-113397 showed antidepressant-like effects in mice. These data suggest that peptide-6 exerts an antidepressant-like effect via inactivation of the central NOP receptor in mice and may represent a lead compound for the development of antidepressant drugs in the future.

脑室注射痛觉肽类似物对小鼠的抗抑郁作用。
阿片受体及其内源性配体是治疗抑郁症的新靶点。痛觉(NOP)受体在结构上与阿片受体相似,但已知NOP对阿片受体亚型μ、δ和κ的亲和力较低。在之前的研究中,我们合成了对阿片受体具有高亲和力的肽,并研究了它们在小鼠体内的抗抑郁样作用。然而,我们还没有研究nop相关的类似物是否有抗抑郁的作用。本研究采用9-氟酰甲基氧羰基(Fmoc)法,以乙酰-精氨酸-酪氨酸-酪氨酸-精氨酸-赖氨酸-赖氨酸-氨2 (ac - ryyrir -氨2)为先导化合物,采用固相多肽法合成NOP类似物(肽-1-肽-8)。我们通过受体结合和小鼠输精管实验检测了NOP受体类似物的亲和力和拮抗活性,并在悬尾试验中检测了它们对静止行为持续时间的影响。肽-6对NOP受体具有较高的亲和力和拮抗活性。小鼠脑室内给药肽-6缩短了不活动行为的持续时间,而同时给药NOP则抑制了这一作用。此外,在小鼠脑室内给予选择性NOP受体拮抗剂J-113397具有抗抑郁样作用。这些数据表明,肽-6通过使小鼠中枢NOP受体失活而发挥抗抑郁样作用,可能是未来抗抑郁药物开发的先导化合物。
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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
247
审稿时长
2 months
期刊介绍: Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.) began publication in 1978 as the Journal of Pharmacobio-Dynamics. It covers various biological topics in the pharmaceutical and health sciences. A fourth Society journal, the Journal of Health Science, was merged with Biol. Pharm. Bull. in 2012. The main aim of the Society’s journals is to advance the pharmaceutical sciences with research reports, information exchange, and high-quality discussion. The average review time for articles submitted to the journals is around one month for first decision. The complete texts of all of the Society’s journals can be freely accessed through J-STAGE. The Society’s editorial committee hopes that the content of its journals will be useful to your research, and also invites you to submit your own work to the journals.
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