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

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  • Maemoto Takuya
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Tada Miho
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Mihara Takuma
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Ueyama Noriko
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Matsuoka Hideaki
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Harada Katsuya
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Yamaji Takayuki
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Shirakawa Kiyoharu
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Kuroda Satoru
    Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Akahane Atsushi
    Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Iwashita Akinori
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Matsuoka Nobuya
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
  • Mutoh Seitaro
    Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.

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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 A2A 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.<br>

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