Pharmacological Characterization of FR194921, a New Potent, Selective, and Orally Active Antagonist for Central Adenosine A₁ Receptors

Abstract

Adenosine A₁ receptors in the brain are believed to play an important role in brain functioning. We have discovered a novel adenosine A₁ receptor antagonist, FR194921 (2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone), and characterized the pharmacological activity in the present study. FR194921 showed potent and selective affinity for the adenosine A₁ receptor without affinity for A_2A and A₃ receptors and did not show any species differences in binding affinity profile among human, rat, and mouse. Pharmacokinetic study in rats revealed that FR194921 was orally active and highly brain penetrable. Oral administration of FR194921 dose-dependently ameliorated the hypolocomotion induced by the A₁ receptor agonist N⁶-cyclopentyladenosine in rats, indicating this compound exerts A₁-antagonistic action in vivo. In the passive avoidance test, scopolamine (1 mg/kg)-induced memory deficits were significantly ameliorated by FR194921 (0.32, 1 mg/kg). In two animal models of anxiety, the social interaction test and elevated plus maze, FR194921 showed specific anxiolytic activity without significantly influencing general behavior. In contrast, FR194921 did not show antidepressant activity even at a dose of 32 mg/kg in the rat forced swimming test. These results indicate that the novel, potent, and selective adenosine A₁ receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of this compound for dementia and anxiety disorders.