Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors
Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors
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DOI：
10.1021/acs.jmedchem.8b01691
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发表时间：
2019-04-11
影响因子：
7.3
通讯作者：
Shuto, Satoshi
中科院分区：
文献类型：
--
作者：
Ichinose, Wataru;Cherepanov, Stanislav M.;Shuto, Satoshi
九肽激素催产素（OT）在社会识别和互动中具有关键的大脑作用，因此是一种有前途的治疗药物。然而，由于其肽结构，OT从血液中迅速消除，这降低了其在大脑中的潜在治疗作用。我们发现，新合成的OT类似物（其中OT的Pro（7）被N-（对氟苄基）甘氨酸（2）或N-（3-羟丙基）甘氨酸（5）取代）通过选择性激活HEK细胞中的OT受体而不是加压素受体，表现出对OT受体的高度有效的结合亲和力和Ca 2+动员作用，其中2被鉴定为OT受体的超激动剂（E-Max = 131%）。此外，两种OT类似物对两种表现出自闭症谱系障碍样社会行为缺陷的CD 38敲除小鼠的社会行为受损恢复具有显著的长效作用，长达16-24小时，而OT本身的作用迅速减弱。
The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro(7) of OT was replaced with N-(p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist (E-Max = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16-24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.