Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB‐1020: Implications for treatment of attention‐deficit hyperactivity disorder

Abstract

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB-1020 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane HCl). EB-1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB-1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB-1020 dose-dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB-1020 dose-dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6-hydroxydopamine (100 μg intracisternally) as neonates; a well-established animal model for attention-deficit hyperactivity disorder (ADHD). These data suggest that EB-1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD.

Development of potent dopamine–norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template

“…[35] It is perceived that a dual DNRI with a potency order of NET>DAT might offer better alternatives to current ADHD therapies. [36] …”

Tph2 gene deletion enhances amphetamine‐induced hypermotility: effect of 5‐HT restoration and role of striatal noradrenaline release

“…; Bymaster et al . ; Umehara et al . ), basal extracellular levels of NA in the striatum were close to or below the limits of quantitation (2 fmol/sample) and at least 2–3 fold lower than in the PFC, reflecting the differences in the density of NA innervations across brain regions (Lindvall and Bjorklund ).…”

One‐Pot Synthesis of Cyclopropane‐Fused Cyclic Amidines: An Oxidative Carbanion Cyclization

“…Heterocyclic ring systems bearing a cyclopropane moiety occur in many biologically active natural products, including alkaloids, terpenes, pheromones, herbicides, and fatty acid metabolites . The 3‐azabicyclo[ n .1.0]alkane framework is present in several pharmaceuticals, such as the antibacterial agent trovafloxacin, the anti‐addiction agent amitifadine, the attention deficit hyperactivity disorder (ADHD) drug candidate centanafadine, the analgesic agent bicifadine, the antidepressant drug candidate GSK1360707, and narlaprevir, a protease‐inhibitor drug for the treatment of hepatitis C virus (HCV) infection (Figure ).As a result of their medicinal applications, several synthetic approaches have been reported for the construction of 3‐azabicyclo[ n .1.0]alkane derivatives…”