title: 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 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.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, Yodogawa-ku, Osaka, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Maemoto
authors.forename: Miho
authors.initials: M
authors.lastname: Tada
authors.forename: Takuma
authors.initials: T
authors.lastname: Mihara
authors.forename: Noriko
authors.initials: N
authors.lastname: Ueyama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Harada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaji
authors.forename: Kiyoharu
authors.initials: K
authors.lastname: Shirakawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Kuroda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Akahane
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwashita
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*
chemical_list: C497088:2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo(1,5-a)pyridin-3-yl)-3(2H)-pyridazinone; D058916:Adenosine A1 Receptor Antagonists; D010880:Piperidines; D011724:Pyridazines; D011725:Pyridines; D043682:Receptor, Adenosine A1; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine