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

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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.