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

Abstract

Abstract. Adenosine A 1 receptors in the brain are believed to play an important role in brain functioning. We have discovered a novel adenosine A 1 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 A 1 receptor without affinity for A 2A and A 3 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 A 1 receptor agonist N 6 -cyclopentyladenosine in rats, indicating this compound exerts A 1 -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 A 1 receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of this compound for dementia and anxiety disorders.

Pharmacological Characterization of the Newly Synthesized Nociceptin/Orphanin FQ–Receptor Agonist 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an Anxiolytic Agent

“…Currently, there is a great deal of interest in developing new drugs with minimal adverse effects to treat anxiety disorders (13,14). Among the candidate approaches, many studies have also suggested that the N/ OFQ peptide and the NOP-receptor system are promising targets (15).…”

Adenosine receptors as therapeutic targets

“…FR194921 was orally active and centrally available, ameliorated scopolamineinduced memory deficits, and also showed anxiolytic effects in the elevated plus maze test, without influencing general behaviour or having antidepressant activity 107 .…”

“…Recently, the novel A 1 AR-selective antagonist FR194921 (which did not show any species differences in its high A 1 AR affinity) was reported to have potential in the treatment of dementia and anxiety disorders 107 . FR194921 was orally active and centrally available, ameliorated scopolamineinduced memory deficits, and also showed anxiolytic effects in the elevated plus maze test, without influencing general behaviour or having antidepressant activity 107 .…”

Die adenosien A₁- en A_2A-reseptoraffiniteit van ’n reeks 3,4-dihidropirimidoon-analoë

“…Die kognitiewe effekte van kafeïen kan merendeels toegeskryf word aan sy vermoë om adenosien A 1 -reseptore in die hippokampus en prefrontale korteks van die brein te antagoniseer (Ribeiro & Sebastião 2010). Hierdie breinareas word normaalweg met kognitiewe funksies geassosieer (Maemoto et al 2004). Adenosien A 1 -antagoniste depolariseer neurone wat postsinapties voorkom en verhoog die presinaptiese vrystelling van 'n aantal neurotransmitters soos asetielcholien, glutamaat, serotonien en norepinefrien.…”