title: Positive allosteric modulation of A1adenosine receptors as a novel and promising therapeutic strategy for anxiety.
abstract: Activation of A1adenosine receptors (ARs) has been associated with anxiolytic-like effects in different behavioral tests, but development of A1AR agonists for therapeutic use has been hampered, most likely due to the presence of side effects. With the aim to identify a safer approach for the treatment of anxiety, we investigated, in mice, the anxiolytic-like properties of a novel A1AR positive allosteric modulator, TRR469. Acute administration of TRR469 (0.3-3 mg/kg) resulted in robust anxiolytic-like effects in the elevated plus maze, the dark/light box, the open field and the marble burying tests. The magnitude of the anxiolytic action of TRR469 was comparable to that obtained with benzodiazepine diazepam (1 mg/kg). The use of the A1AR antagonist DPCPX (3 mg/kg) suggested that the effects of TRR469 were mediated by this receptor subtype. In contrast to diazepam, the novel positive allosteric modulator did not potentiate the sedative effect of ethanol (3.5 g/kg) evaluated by the loss of righting reflex. While diazepam produced motor coordination impairment in the rotarod test, this effect being enhanced by the presence of ethanol (1.5 g/kg), TRR469 did not elicit locomotor disturbances either when administered alone or in the presence of ethanol. In vitro, TRR469 was able to increase the number of A1AR recognizable by the agonist radioligand [3H]-CCPA in mouse brain regions involved in emotional processes. TRR469 markedly increased the affinity of the agonist CCPA, suggesting the capability, in vivo, to increase the affinity of endogenous adenosine. Taken together, these findings indicate that the positive allosteric modulation of A1AR may represent a promising approach for the treatment of anxiety-related disorders.
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Ravani
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pasquini
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address: vrk@unife.it.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D058907:Adenosine A1 Receptor Agonists / Q000008:administration & dosage*; D058916:Adenosine A1 Receptor Antagonists / Q000008:administration & dosage; D000494:Allosteric Regulation; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001008:Anxiety Disorders / Q000188:drug therapy*; D003975:Diazepam / Q000008:administration & dosage; D000431:Ethanol / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D057897:Reflex, Righting / Q000187:drug effects; D045442:Rotarod Performance Test; D013876:Thiophenes / Q000008:administration & dosage*; D014970:Xanthines / Q000008:administration & dosage
chemical_list: C000593530:2-amino-4-((4-(phenyl)piperazin-1-yl)methyl)-5-(4-fluorophenyl)thiophen-3-yl)-(4-chlorophenyl)methanone; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D014151:Anti-Anxiety Agents; D010879:Piperazines; D043682:Receptor, Adenosine A1; D013876:Thiophenes; D014970:Xanthines; C058394:2-chloro-N(6)cyclopentyladenosine; D000431:Ethanol; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D003975:Diazepam
keywords: A1 receptors; Adenosine; Anxiety; Benzodiazepines; Positive allosteric modulation; TRR469