Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder.
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.
Euthymics Bioscience Inc., Thorndike St Suite S1-3, Cambridge, MA 02141, USA. fbymaster@euthymics.com
Frank P
FP
Bymaster
Krystyna
K
Golembiowska
Magdalena
M
Kowalska
Yong Kee
YK
Choi
Frank I
FI
Tarazi
D000375:Aging; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000378:metabolism*; D053961:Azabicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019417:Hindlimb Suspension; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
C574080:1-(naphthalen-2-yl)-3-azabicyclo(3.1.0)hexane; D053961:Azabicyclo Compounds; D018765:Dopamine Uptake Inhibitors; D009281:Naphthalenes; D004298:Dopamine; D009638:Norepinephrine