PMID- 25941078
OWN - NLM
STAT- MEDLINE
DCOM- 20160517
LR  - 20191210
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 761
DP  - 2015 Aug 15
TI  - Characterisation of Lu AF33241: A novel, brain-penetrant, dual inhibitor of 
      phosphodiesterase (PDE) 2A and PDE10A.
PG  - 79-85
LID - S0014-2999(15)00399-4 [pii]
LID - 10.1016/j.ejphar.2015.04.040 [doi]
AB  - 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.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Redrobe, John P
AU  - Redrobe JP
AD  - Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, 
      Denmark. Electronic address: JOPR@lundbeck.com.
FAU - Rasmussen, Lars K
AU  - Rasmussen LK
AD  - Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, 
      Denmark.
FAU - Christoffersen, Claus T
AU  - Christoffersen CT
AD  - Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, 
      Denmark.
FAU - Bundgaard, Christoffer
AU  - Bundgaard C
AD  - Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, 
      Denmark.
FAU - Jorgensen, Morten
AU  - Jorgensen M
AD  - Neuroscience Research DK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Copenhagen, 
      Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150502
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Lu AF33241)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Quinoxalines)
RN  - 0 (Triazoles)
RN  - EC 3.1.4.- (PDE10A protein, human)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2)
RN  - EC 3.1.4.17 (PDE2A protein, human)
SB  - IM
MH  - Animals
MH  - Antipsychotic Agents/metabolism/*pharmacology/toxicity
MH  - Avoidance Learning/drug effects
MH  - Behavior, Animal/*drug effects
MH  - Blood-Brain Barrier/*metabolism
MH  - Capillary Permeability
MH  - Catalepsy/chemically induced
MH  - Cognition/drug effects
MH  - Cyclic Nucleotide Phosphodiesterases, Type 2/*antagonists & inhibitors/metabolism
MH  - Exploratory Behavior/drug effects
MH  - Humans
MH  - Male
MH  - Motor Activity/drug effects
MH  - Phosphodiesterase Inhibitors/metabolism/*pharmacology/toxicity
MH  - Phosphoric Diester Hydrolases/*metabolism
MH  - Quinoxalines/metabolism/*pharmacology
MH  - Rats, Sprague-Dawley
MH  - Rats, Wistar
MH  - Recognition, Psychology/drug effects
MH  - Triazoles/metabolism/*pharmacology
OTO - NOTNLM
OT  - Antipsychotic
OT  - Cognition
OT  - Inhibitor
OT  - PDE10A
OT  - PDE2A
OT  - Schizophrenia
EDAT- 2015/05/06 06:00
MHDA- 2016/05/18 06:00
CRDT- 2015/05/06 06:00
PHST- 2015/01/09 00:00 [received]
PHST- 2015/04/01 00:00 [revised]
PHST- 2015/04/16 00:00 [accepted]
PHST- 2015/05/06 06:00 [entrez]
PHST- 2015/05/06 06:00 [pubmed]
PHST- 2016/05/18 06:00 [medline]
AID - S0014-2999(15)00399-4 [pii]
AID - 10.1016/j.ejphar.2015.04.040 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2015 Aug 15;761:79-85. doi: 10.1016/j.ejphar.2015.04.040. Epub 
      2015 May 2.