Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by hyperactivity, inattention and impulsivity. Psychostimulants, including methylphenidate and amphetamines, are commonly used to alleviate symptoms of ADHD. However, these medications are typically associated with undesirable side effects, prompting the search for novel non-psychostimulant treatments for ADHD. A major recent discovery from our laboratory is that locomotor hyperactivity in juvenile rats lesioned with 6-hydroxy-dopamine (6- OHDA) as neonates was reversed in dose-dependent manner by highly selective dopamine (DA) D4 receptor antagonists (CP-293,019, 1745,870, U-101,958). These findings accord with a repeatedly reported genetic association of specific D4 receptor polymorphic variant and ADHD, and implicate D4 receptor antagonists as attractive agents for managing hyperactivity in ADHD. However, there is no clinical evidence that D4 antagonists can improve attention or other cognitive deficits in ADHD patients. Recent studies suggested that the non-stimulant agent modafinil improves attention and cognitive deficits, but not hyperactivity, in ADHD patients. Therefore D4 antagonists or modafinil alone may not be adequate for effectively managing all core symptoms of ADHD. We propose to synthesize and extensively evaluate novel hybrid compounds combining core structural features of both D4-selective antagonists and modafinil. The pharmacological profile of these hybrid compounds will be characterized by determining their affinity to DA D4 and adrenergic a1 receptors, to other DA and serotonin receptors and to monoamine transporters, as well as their molecular functionality at D4 and a1 receptors. The behavioral effects of novel selected compounds that display full D4 antagonistic and a1 agonistic properties will be assessed in two behavioral paradigms: (i) locomotor activity in juvenile hyperactive rats lesioned with 6-OHDA as neonates, and (ii) sustained attention in rats using a five-choice serial reaction time task to determine their efficacy in reversing locomotor hyperactivity and enhancing performance of sustained attention in both spatial and temporal domains. Expected findings should evolve new principles and lead to the development of much-needed novel drugs that are effective in managing the core behavioral and attention dysfunctions of ADHD and other neuropsychiatric disorders, with superior safety and tolerability. ? ? ?
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