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Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT (1A) receptor antagonist and potential novel antidepressant.
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.
Afiliación
  • Beyer CE; Discovery Neuroscience, Wyeth Research, Princeton, NJ 08543-8000, USA. beyerc1@wyeth.com
Br J Pharmacol ; 157(2): 307-19, 2009 May.
Article en En | MEDLINE | ID: mdl-19338583
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 GTPgammaS). 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antagonistas de la Serotonina / Inhibidores Selectivos de la Recaptación de Serotonina / Antidepresivos de Segunda Generación / Antagonistas del Receptor de Serotonina 5-HT1 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2009 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antagonistas de la Serotonina / Inhibidores Selectivos de la Recaptación de Serotonina / Antidepresivos de Segunda Generación / Antagonistas del Receptor de Serotonina 5-HT1 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2009 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido