EVALUATION OF A NOVEL H3 ANTAGONIST, GT-2016, FOR ADHD

长期目标是开发新型组胺H3受体 用于注意力缺陷多动障碍（ADHD）的拮抗剂， 相关的认知疾病。 具体目标（第1年）：（1） 合成 克量的稳定GT-2016盐用于体内扩增 试验. GT- 2016年盐将与临床使用的ADHD药物进行比较 （哌醋甲酯，d-苯丙胺和匹莫林）在3个行为 模型 功效 （2）中H3拮抗剂在发育上的比较 未成熟的幼年大鼠幼仔（3）6-OH DA大鼠ADHD模型和（4） 基于遗传的ADHD SNAP（CM）小鼠模型将提供3种啮齿动物 模型 认知和/或活动结果。 此外，脑电图分析在 （五） 正常大鼠和（6）发作性睡眠狗将提供唤醒， 警惕 评估、一般行为、心血管和呼吸 结果。 第二年的具体目标将包括研究确定 药物作用的特异性和安全性。 其中包括：（7） 药物 滥用可能性研究，（8）致突变试验，（9）14 C-GT-2016 分布研究和代谢产物鉴别，（10） 药代动力学，（11）药物代谢和肝脏诱导 配置文件和 (12)毒理学测试 这项研究将是第一个 识别 H3拮抗剂在治疗认知障碍中的效用 障碍 包括ADHD，并为临床提供有价值的信息 发展

The long-term objectives are to develop novel histamine H3 receptor antagonists for attention deficit hyperactive disorders (ADHD) and related cognitive diseases. Specific Aims are (year 1): (1) synthesis of gram quantities of stable GT-2016 salt for expanded in vivo testing. GT- 2016 salt will be compared versus clinically utilized ADHD agents (methylphenidate, d-amphetamine and pemoline) in 3 behavioral models for efficacy. Comparisons of the H3 antagonist in (2) developmentally immature juvenile rat pups (3) a 6-OH DA rat ADHD model and (4) a genetic-based ADHD SNAP(CM) mouse model will provide 3 rodent models with cognitive and/or activity outcomes. Additionally, EEG profiling in (5) normal rats and (6) narcoleptic dogs will provide arousal and vigilant assessments, general behavioral, cardiovascular and respiratory outcomes. Specific Aims for year 2 would involve studies determining the specificity and safety of the drugs' actions. These include: (7) drug abuse potential studies, (8) mutagenesis testing, (9) 14C-GT-2016 distribution studies and metabolite identification, (10) pharmacokinetics, (11) drug metabolism and liver induction profiles, and (12) toxicological testing. This research would be the first to identify the utility of H3 antagonists in the treatment of cognitive disorders including ADHD and provide valuable information towards clinical development.