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

• DOI: 10.1124/jpet.108.149617
• Publication Date: 2009-03-31T00:56:51Z
• Authors: Robert A. Hodgson; Rosalia Bertorelli; Geoffrey B. Varty; Jean E. Lachowicz; Angelo Forlani; Silva Fredduzzi; Mary E. Cohen-Wil...; Guy A. Higgins; Francesco Impagna...; Elisa Nicolussi; Leonard E. Parra; Carolyn Foster; Ying Zhai; Bernie R. Neustadt; Andrew W. Stamford; Eric M. Parker; Angelo Reggiani; John C. Hunter
• Keywords: Raclopride

The adenosine A_2A receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson9s disease (PD) depression. Preladenant SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7<i>H</i>-pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]pyrimidin-5-amine] are potent competitive antagonists human (<i>K</i>_i = 1.1 0.6 nM, respectively) have &gt;1000-fold selectivity over all other receptors, making these compounds most selective reported to date. Both attenuate hypolocomotion induced by agonist CGS-21680 [2-[<i>p</i>-(2-carboxyethyl)phenethylamino]-5′-<i>N</i>-ethylcarboxamidoadenosine], suggesting that they inhibit activity vivo. Their high degree robust vivo make preladenant useful tools investigate role system animal models PD Oral administration (0.1–1 mg/kg) rats potentiated 3,4-dihydroxy-l-phenylalanine (l-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions medial forebrain bundle potently attenuated cataleptic effects haloperidol. (1 inhibited l-Dopa-induced behavioral sensitization repeated daily administration, which suggests a reduced risk development dyskinesias. Finally, exhibited antidepressant-like profiles despair, namely mouse tail suspension test rat forced swim test. These studies demonstrate provide further evidence potential therapeutic benefits inhibition (with dyskinesias) depression (one primary nonmotor symptoms PD).