WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression.
OBJECTIVE
Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.


METHODS
In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one).


RESULTS
WAY-318068 is a potent and effective inhibitor of the NET with a K(i) of 8.7 nM in a binding assay, and an IC(50) of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.


CONCLUSIONS
Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.
Whiteside
G T
GT
Pfizer Global Research and Development, Neuroscience, Princeton, NJ 08540, USA. garth_whiteside@yahoo.com
Dwyer
J M
JM
Harrison
J E
JE
Beyer
C E
CE
Cummons
T
T
Manzino
L
L
Mark
L
L
Johnston
G H
GH
Strassle
B W
BW
Adedoyin
A
A
Lu
P
P
Piesla
M J
MJ
Pulicicchio
C M
CM
Erve
J C L
JC
Platt
B J
BJ
Hughes
Z A
ZA
Rogers
K E
KE
Deecher
D C
DC
Trybulski
E J
EJ
Kennedy
J D
JD
Zhang
P
P
Leventhal
L
L
D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010146:Pain; D010147:Pain Measurement / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D007211:Indoles; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C552598:WAY-318068