Preclinical characterization of WAY-211612: A dual 5-HT uptake inhibitor and 5-HT 1A receptor antagonist and potential novel antidepressant

Abstract

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; l max 100% in adenyl cyclase assays; K B = 19.8 nmol-L -1; l max 100% in CTPγS). 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, l.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-lnduced polydipsia model. Conclusions and Implications: These findings suggest that WAY-211612 may represent a novel antidepressant. © 2009 The British Pharmacological Society All rights reserved.