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- Title
Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT (1A) receptor antagonist and potential novel antidepressant.
- Authors
Beyer, C. E.; Lin, Q.; Platt, B.; Malberg, J.; Hornby, G.; Sullivan, K. M.; Smith, D. L.; Lock, T.; Mitchell, P. J.; Hatzenbuhler, N. T.; Evrard, D. A.; Harrison, B. L.; Magolda, R.; Pangalos, M. N.; Schechter, L. E.; Rosenzweig-Lipson, S.; Andree, T. H.
- Abstract
Background and purpose: As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT1A 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 (Ki = 1.5 nmol·L−1; KB = 17.7 nmol·L−1) and exhibited full 5-HT1A receptor antagonist activity (Ki = 1.2 nmol·L−1; KB = 6.3 nmol·L−1; Imax 100% in adenyl cyclase assays; KB = 19.8 nmol·L−1; Imax 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-HT1A 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-HT1A 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.
- Subjects
ANTIDEPRESSANTS; SEROTONIN uptake inhibitors; PREFRONTAL cortex; FLUOXETINE; BIOCHEMISTRY; ANIMAL behavior; HIGH performance liquid chromatography; CYCLIC adenylic acid; SEROTONIN antagonists; RATS; SECOND-generation antidepressants; HEMODIALYSIS; MICE; ANIMALS; PHARMACODYNAMICS
- Publication
British Journal of Pharmacology, 2009, Vol 157, Issue 2, p307
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1111/j.1476-5381.2009.00146.x