Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920:: II.: In vivo behavioral and neurophysiological characterization
Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920:: II.: In vivo behavioral and neurophysiological characterization
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DOI：
10.1124/jpet.102.047241
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发表时间：
2003-06-01
影响因子：
3.5
通讯作者：
Hancock, AA
中科院分区：
文献类型：
--
作者：
Fox, GB;Pan, JB;Hancock, AA
中枢组胺H-3受体（H（3）Rs）的药理学阻断可增强啮齿类动物的认知能力，并为神经系统疾病的临床治疗提供了希望。然而，许多先前表征的H3 R拮抗剂对H（3）Rs没有选择性或具有潜在的显著耐受性问题。在这里，我们提出了在体内的行为和神经生理学数据的两种新的和选择性的H3 R拮抗剂与改善的安全指数。A-304121首次证实了中枢H（3）Rs的功能性阻断[（4-（3-（4-（（2 R）-2-氨基丙酰基）-1-哌嗪基）丙氧基）苯基）环丙基甲酮]（1 mg/kg）和A-317920 [N-（（1 R）-2-氨基丙酰基）-1-哌嗪基）丙氧基]（4-（3-（4-（环丙基羰基）苯氧基）丙基）-1-哌嗪基）-1-甲基-2-氧代-乙基）-2-呋喃酰胺]（0.45 mg/kg）通过显著减弱对选择性H3 R激动剂（R）-α-甲基组胺[（R）-α-MeHA]的急性致渴反应。A-304121给药后，在5次试验大鼠幼仔回避试验中，认知表现得到改善（10 mg/kg）或A-317920（3 mg/kg），疗效与之前发表的参考H3 R拮抗剂硫代哌丁胺的观察结果相当（10 mg/kg）、环丙昔凡（3 mg/kg）和GT-2331 [（1 R，2 R）-4-（2-（5，5-二甲基己-1-炔基）环丙基）咪唑]（1 mg/kg）。A-304121（3、10 mg/kg）和A-317920（1、3 mg/kg）在未引起脑电图慢波振幅活动显著变化的剂量下也显著增强了成年大鼠的社会记忆。通过比较一般观察研究中产生不良反应的剂量与抑制性回避效力，估计A-304121和A-317920的相对治疗指数（TI）分别为30和42，其上级优于参比拮抗剂硫代哌丁胺、环丙昔芬和GT-2331观察到的TI分别为8、10和18。A-304121和A-317920代表了一系列新的H3 R选择性哌嗪酰胺，可增强体内认知，其可提供优于现有H3 R拮抗剂或认知增强剂的优势。
Pharmacological blockade of central histamine H-3 receptors (H(3)Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H(3)Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices. Functional blockade of central H(3)Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1- piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy) propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an acute dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA]. Cognitive performance was improved in a five-trial rat pup avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3 mg/kg), with efficacy comparable with previously published observations for reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl) cyclopropyl) imidazole] (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H3R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H3R antagonists or cognition-enhancing agents.