ABSTRACT
Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 1/antagonists & inhibitors , Goals , Phencyclidine/toxicity , Phosphodiesterase Inhibitors/therapeutic use , Prefrontal Cortex/enzymology , Schizophrenia/enzymology , Animals , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Cyclic Nucleotide Phosphodiesterases, Type 1/metabolism , Disease Models, Animal , Female , Hallucinogens/toxicity , Phosphodiesterase Inhibitors/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiopathology , Rats , Schizophrenia/chemically induced , Schizophrenia/drug therapyABSTRACT
BACKGROUND AND PURPOSE: PDE1, a subfamily of cyclic nucleotide PDEs consisting of three isoforms, PDE1A, PDE1B and PDE1C, has been implicated in the regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform-preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896 and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone. EXPERIMENTAL APPROACH: In rat mesenteric arteries, expression and localization of Pde1 isoforms were determined by quantitative PCR and in situ hybridization, and physiological impact of PDE1 inhibition was evaluated by isometric tension recordings. KEY RESULTS: In rat mesenteric arteries, Pde1a mRNA expression was higher than Pde1b and Pde1c. In situ hybridization revealed localization of Pde1a to vascular smooth muscle cells (VSMCs) and only minor appearance of Pde1b and Pde1c. The potency of the PDE1 inhibitors at eliciting relaxation showed excellent correlation with their potency at inhibiting PDE1A. Thus, Lu AF58027 was the most potent at inhibiting PDE1A and was also the most potent at eliciting relaxation in mesenteric arteries. Inhibition of NOS with l-NAME, soluble GC with ODQ or PKG with Rp-8-Br-PET-cGMP all attenuated the inhibitory effect of PDE1 on relaxation, whereas PKA inhibition with H89 had no effect. CONCLUSIONS AND IMPLICATIONS: Pde1a is the dominant PDE1 isoform present in VSMCs, and relaxation mediated by PDE1A inhibition is predominantly driven by enhanced cGMP signalling. These results imply that isoform-selective PDE1 inhibitors are powerful investigative tools allowing examination of physiological and pathological roles of PDE1 isoforms.
Subject(s)
Cyclic GMP/physiology , Cyclic Nucleotide Phosphodiesterases, Type 1/antagonists & inhibitors , Mesenteric Arteries/physiology , Animals , Cyclic Nucleotide Phosphodiesterases, Type 1/genetics , Cyclic Nucleotide Phosphodiesterases, Type 1/physiology , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Isoenzymes/physiology , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/enzymology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/enzymology , Myocytes, Smooth Muscle/physiology , Phosphodiesterase Inhibitors/pharmacology , Rats, Wistar , Vasodilation/drug effectsABSTRACT
The formation of 1,5-disubstituted 1,2,3-triazoles from aryl azides and alkynes was readily accomplished using [Cp*RuCl]4 catalyst in dimethylformamide. It was also demonstrated that the reaction provided higher yields, cleaner product, and shorter reaction times when carried out under microwave irradiation.
Subject(s)
Alkynes/chemistry , Azides/chemistry , Ruthenium/chemistry , Catalysis , CyclizationABSTRACT
Novel nonsymmetrical N-bi- and N-terarylpiperazines were synthesized on solid phase via three consecutive palladium-catalyzed cross-coupling reactions in which C-N, C-B, and C-C bonds are formed consecutively.
