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Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression.
Hodgson, Robert A; Bertorelli, Rosalia; Varty, Geoffrey B; Lachowicz, Jean E; Forlani, Angelo; Fredduzzi, Silva; Cohen-Williams, Mary E; Higgins, Guy A; Impagnatiello, Francesco; Nicolussi, Elisa; Parra, Leonard E; Foster, Carolyn; Zhai, Ying; Neustadt, Bernie R; Stamford, Andrew W; Parker, Eric M; Reggiani, Angelo; Hunter, John C.
Afiliación
  • Hodgson RA; Departments of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Robert.Hodgson@SPCorp.com
J Pharmacol Exp Ther ; 330(1): 294-303, 2009 Jul.
Article en En | MEDLINE | ID: mdl-19332567
ABSTRACT
The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A(2A) receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A(2A) receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine], suggesting that they inhibit A(2A) receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Triazoles / Fármacos Neuroprotectores / Trastorno Depresivo / Modelos Animales de Enfermedad / Antagonistas del Receptor de Adenosina A2 / Trastornos del Movimiento Límite: Animals / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2009 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Triazoles / Fármacos Neuroprotectores / Trastorno Depresivo / Modelos Animales de Enfermedad / Antagonistas del Receptor de Adenosina A2 / Trastornos del Movimiento Límite: Animals / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2009 Tipo del documento: Article País de afiliación: Estados Unidos