title: In vitro and in vivo characterisation of Lu AF64280, a novel, brain penetrant phosphodiesterase (PDE) 2A inhibitor: potential relevance to cognitive deficits in schizophrenia.
abstract: Here, we present the pharmacological characterisation of Lu AF64280, a novel, selective, brain penetrant phosphodiesterase (PDE) 2A inhibitor, in in vitro/in vivo assays indicative of PDE2A inhibition, and in vivo models/assays relevant to cognitive processing or antipsychotic-like activity. The in vitro selectivity of Lu AF64280 was determined against a panel of PDE enzymes and 3',5'-cyclic guanosine monophosphate (cGMP) levels in the hippocampus were determined using in vivo microdialysis. Lu AF64280 potently inhibited hPDE2A (Ki = 20 nM), 50-fold above moderate inhibition of both hPDE9A (Ki = 1,000 nM) and hPDE10A (Ki = 1,800 nM), and displayed a >250-fold selectivity over all other full-length human recombinant PDE family members (Ki above 5,000 nM). Lu AF64280 (20 mg/kg) significantly increased cGMP levels in the hippocampus (p < 0.01 versus vehicle-treated mice), attenuated sub-chronic phencyclidine-induced deficits in novel object exploration in rats (10 mg/kg, p < 0.001 versus vehicle-treated), blocked early postnatal phencyclidine-induced deficits in the intradimensional/extradimensional shift task in rats (1 and 10 mg/kg, p < 0.001 versus vehicle-treated) and attenuated spontaneous P20-N40 auditory gating deficits in DBA/2 mice (20 mg/kg, p < 0.05 versus vehicle-treated). In contrast, Lu AF64280 failed to attenuate phencyclidine-induced hyperactivity in mice, and was devoid of antipsychotic-like activity in the conditioned avoidance response paradigm in rats, at any dose tested. Lu AF64280 represents a novel tool compound for selective PDE2A inhibition that substantiates a critical role of this enzyme in cognitive processes under normal and pathological conditions.
authors.affiliation: Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, Valby, 2500, Copenhagen, Denmark.
authors.forename: John P
authors.initials: JP
authors.lastname: Redrobe
authors.forename: Morten
authors.initials: M
authors.lastname: Jørgensen
authors.forename: Claus T
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: Liliana P
authors.initials: LP
authors.lastname: Montezinho
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.forename: Martin
authors.initials: M
authors.lastname: Carnerup
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.forename: Linda
authors.initials: L
authors.lastname: Lerdrup
authors.forename: Niels
authors.initials: N
authors.lastname: Plath
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology* / Q000523:psychology*; D006152:Cyclic GMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects; D011994:Recombinant Proteins; D012559:Schizophrenia / Q000150:complications* / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D006576:Heterocyclic Compounds, 4 or More Rings; C000599970:Lu AF64280; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D006152:Cyclic GMP; D010622:Phencyclidine