Characterisation of Lu AF33241: A novel, brain-penetrant, dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A.
Here, we present a preliminary pharmacological characterisation of Lu AF33241, a novel, brain penetrant phosphodiesterase inhibitor of (PDE) 2A and 10A tool compound, in in vitro/in vivo assays indicative of PDE2A and/or PDE10A inhibition, and in vivo models/assays relevant to cognitive processing and antipsychotic-like activity. An assay was also included to investigate potential effects on motor activity. The in vitro selectivity of Lu AF33241 was determined against a panel of PDE enzymes. Lu AF33241 potently inhibited both full-length recombinant hPDE2A (Ki=4.2nM) and hPDE10A (Ki=42nM). The compound moderately inhibited both hPDE1C (Ki=1200nM), hPDE7B (Ki=890nM), and hPDE11A (Ki=1800nM). Lu AF33241 displayed a Ki above 5000nM against all other tested members of the PDE family. Albeit within a narrow dose range, Lu AF33241 attenuated sub-chronic phencyclidine-induced deficits in novel object recognition (3 and 10mg/kg), displayed antipsychotic-like activity in the conditioned avoidance response paradigm (10mg/kg), and did not induce catalepsy within a dose-range of 2-6mg/kg. Further catalepsy studies are needed to investigate a predictive safety window. Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool compound that may serve to further the understanding of the roles played by these enzymes in various CNS disorders.
Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark. Electronic address: JOPR@lundbeck.com.
John P
JP
Redrobe
Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark.
Lars K
LK
Rasmussen
Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark.
Claus T
CT
Christoffersen
Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark.
Christoffer
C
Bundgaard
Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark.
Morten
M
Jørgensen
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D002375:Catalepsy / Q000139:chemically induced; D003071:Cognition / Q000187:drug effects; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*
D014150:Antipsychotic Agents; C000607544:Lu AF33241; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; D014230:Triazoles; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human
Antipsychotic; Cognition; Inhibitor; PDE10A; PDE2A; Schizophrenia