Shelly Ann Glase

Design and synthesis of reboxetine analogs morpholine derivatives as selective norepinephrine reuptake inhibitors.

As part of a discovery effort aimed at identifying novel norepinephrine reuptake inhibitors (NRIs), a number of substituted morpholines were designed and synthesized. The target compounds contain vicinal stereogenic centers, and the program was greatly facilitated by the adoption of efficient synthetic routes which allowed for the late stage incorporation of structural and physicochemical diversity into the targets. Structure-activity relationships were developed by optimizing individual ring components of the structure for NRI potency and for selectivity against other monoamine reuptake transporters. Several novel morpholine derivatives with a potent and selective NRI profile are described.

Attention Deficit Hyperactivity Disorder: Pathophysiology and Design of New Treatments

Publisher Summary This chapter presents new therapeutic approaches for the treatment attention-deficit/hyperactivity disorder (ADHD) such as monoamine reuptake inhibitors, Dopamine D 4 antagonists, α 2 -Adrenergic agonists, histamine H 3 antagonists, and nicotinic receptor agonists. There is considerable documentation supporting the association between the 7-repeat allele of the dopamine D 4 receptor and the personality trait of novelty seeking and ADHD, especially the inattention subtype. It has been shown that motor hyperactivity in 6-hydroxydopamine lesioned juvenile rats can be dose-dependently inhibited by stimulants used to treat ADHD and selective antagonists for the dopamine D 4 but not D2 receptors. The α 2 -adrenergic agonists clonidine and guanfacine have been used in the treatment of ADHD especially where co-morbid tic disorders can be exacerbated by stimulants. The synthesis and release of histamine, H 3 receptors are heteroreceptors that modulate the release of a number of other neurotransmitters that are implicated in the learning and motor disturbances in ADHD; these include DA, NE and acetylcholine. H3 antagonists have been shown to enhance attention and cognition in multiple animal models.