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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >SAR110894, a potent histamine H 3-receptor antagonist, displays procognitive effects in rodents
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SAR110894, a potent histamine H 3-receptor antagonist, displays procognitive effects in rodents

机译：SAR110894，一种有效的组胺H 3受体拮抗剂，在啮齿动物中表现出认知作用

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SAR110894 is a novel histamine H 3-R ligand, displaying high and selective affinity for human, rat or mouse H 3-Rs. SAR110894 is a potent H 3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H 3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β 25-35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.
机译：SAR110894是一种新型的组胺H 3-R配体，对人，大鼠或小鼠的H 3-R具有很高的选择性亲和力。 SAR110894是一种天然受体的有效H 3-R拮抗剂，可逆转R-α-甲基组胺对豚鼠回肠中电场刺激收缩的抑制作用。此外，SAR110894抑制人H 3-Rs上的本构GTPγS结合，表现出反向激动剂特性。在针对与精神分裂症（CIAS）和注意力缺陷/多动障碍（ADHD）相关的认知障碍的某些方面的行为模型中，SAR110894改善了小鼠对象识别任务的几种变体（0.3-3 mg / kg，po）或大鼠（0.3-1 mg / kg，口服）。此外，SAR110894（1 mg / kg，口服）在急性迷迭香中的小鼠低剂量的苯环利定（PCP）（0.5 mg / kg，ip）急性重复剂量经反复用A致敏后，在Y迷宫测试中逆转了工作记忆的不足。高剂量的五氯苯酚（10 mg / kg，ip）。在潜伏抑制（LI）模型中，SAR110894增强了盐水处理的大鼠（1和3 mg / kg，腹腔注射）的LI，并逆转了啮齿类动物对新生儿一氧化氮合酶（NOS）的抑制所诱导的异常持续性LI（0.3-3 mg / kg公斤，ip）。在大鼠的社交新奇辨别任务中，SAR110894减轻了新生儿PCP治疗（3和10 mg / kg，p.o。）或该程序的参数修改（3和10 mg / kg，p.o。）引起的选择性注意缺陷。 SAR110894在与阿尔茨海默氏病（AD）认知缺陷有关的几种动物模型中显示出功效。它可以防止东pol碱在大鼠中（0.01-10 mg / kg，口服）或在小鼠的物体识别测试中集中输注有毒淀粉样蛋白片段β25-35（1和3 mg / kg公斤）。总而言之，这些发现表明SAR110894对于治疗AD，精神分裂症和ADHD某些方面的认知症状可能具有治疗意义。

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