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

长期目标是开发新型组胺H3受体 注意力缺陷多动障碍(ADHD)拮抗剂和 相关的认知疾病。具体目标是(一年级)：(一) 一种新的合成方法 克量稳定的GT-2016体内膨化盐 测试。GT- 2016年的SALT将与临床使用的ADHD药物进行比较 (醋酸甲酯、D-苯丙胺和匹莫林)3例 型号： 功效。H3拮抗剂在发育中的比较(2) 幼龄大鼠幼鼠(3)6-羟多巴胺ADHD模型和(4)a 基于遗传的ADHD SNAP(CM)小鼠模型将提供3只啮齿动物 型号： 认知和/或活动结果。此外，中的脑电分析 (5) 正常大鼠和(6)发作性睡病犬将提供觉醒和 警惕 评估、一般行为、心血管和呼吸系统 结果。 第二年的具体目标将涉及确定 药物作用的特异性和安全性。这些措施包括：(7) 药物 滥用潜力研究，(8)诱变测试，(9)14C-GT-2016 分布研究和代谢物鉴定(10) 药代动力学，(11)药物代谢和肝脏诱导 配置文件，和 (12)毒理试验。这项研究将是第一次 识别 H3受体拮抗剂在认知障碍治疗中的应用 疾患 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.