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WAY‐318068: a novel, potent and selective noradrenaline re‐uptake inhibitor with activity in rodent models of pain and depression
Author(s) -
Whiteside GT,
Dwyer JM,
Harrison JE,
Beyer CE,
Cummons T,
Manzino L,
Mark L,
Johnston GH,
Strassle BW,
Adedoyin A,
Lu P,
Piesla MJ,
Pulicicchio CM,
Erve JCL,
Platt BJ,
Hughes ZA,
Rogers KE,
Deecher DC,
Trybulski EJ,
Kennedy JD,
Zhang P,
Leventhal L
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00690.x
Subject(s) - pharmacology , transporter , microdialysis , in vivo , neuropathic pain , norepinephrine transporter , chemistry , dopamine , medicine , pharmacokinetics , norepinephrine , biology , biochemistry , microbiology and biotechnology , gene
Background and purpose: 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. Experimental approach: 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‐[(1 S ,2 R )‐1‐(3,5‐difluorophenyl)‐2‐hydroxy‐3‐(methylamino)propyl]‐7‐fluoro‐3,3‐dimethyl‐1,3‐dihydro‐2 H ‐indol‐2‐one). Key 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 and implications: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.