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-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-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 IC50 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.

Background and purpose: As a combination of 5‐HT selective reuptake inhibitor (SSRI) with 5‐HT 1A receptor antagonism may yield a rapidly acting antidepressant, WAY‐211612, a compound with both SSRI and 5‐HT 1A receptor antagonist activities, was evaluated in preclinical models. Experimental approach: Occupancy studies confirmed the mechanism of action of WAY‐211612, while its in vivo profile was characterized in microdialysis and behavioural models. Key results: WAY‐211612 inhibited 5‐HT reuptake (K i = 1.5 nmol·L −1 ; K B = 17.7 nmol·L −1 ) and exhibited full 5‐HT 1A receptor antagonist activity (K i = 1.2 nmol·L −1 ; K B = 6.3 nmol·L −1 ; I max 100% in adenyl cyclase assays; K B = 19.8 nmol·L −1 ; I max 100% in GTPγS). WAY‐211612 (3 and 30 mg·kg −1 , po) occupied 5‐HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5‐HT 1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY‐211612 (3–30 mg·kg −1 , po) raised levels of cortical 5‐HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg −1 , s.c.) and a 5‐HT 1A antagonist (WAY‐100635; 0.3 mg·kg −1 , s.c). WAY‐211612 (3.3–30 mg·kg −1 , s.c.) decreased aggressive behaviour in the resident‐intruder model, while increasing the number of punished crossings (3–30 mg·kg −1 , i.p. and 10–56 mg·kg −1 , po) in the mouse four‐plate model and decreased adjunctive drinking behaviour (56 mg·kg −1 , i.p.) in the rat scheduled‐induced polydipsia model. Conclusions and implications: These findings suggest that WAY‐211612 may represent a novel antidepressant.