Expression of the cGMP‐specific phosphodiesterases 2 and 9 in normal and Alzheimer's disease human brains

Reyes-Irisarri, Elisabet; Ittersum, Marjanne Markerink‐van; Mengod, Guadalupe; Vente, Jan de

doi:10.1111/j.1460-9568.2007.05589.x

Cited by 101 publications

(87 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PDE2A is one of the 11 known PDE families and is highly expressed in brain regions such as the striatum, hippocampus, and frontal cortex, which are closely linked to emotion, learning, and memory. [13][14][15][16][17][18] In addition, PDE2A has been shown to hydrolyze the intracellular second messengers, cAMP and 3′,5′-cyclic guanosine monophosphate (cGMP), 19) molecules that play important roles in regulating cyclic nucleotide signaling implicated in neuronal plasticity and memory. [20][21][22][23][24] In light of these features, it is hypothesized that inhibition of PDE2A could exert procognitive activity through augmentation of cyclic nucleotide signaling in the aforementioned brain areas, thus leading to the treatment of cognitive dysfunction in a range of neuropsychiatric and neurodegenerative disorders.…”

Section: These Efforts Resulted In the Discovery Of N-((1s)-2-hydroxymentioning

confidence: 99%

“…7, compound 20 dose-dependently occupied PDE2A in rat striatum with a 50% target occupancy oral dose (ED 50 ) of 3.9 mg/kg. Based on these results, cyclic nucleotide levels in the frontal cortex, hippocampus, and striatum of rat brain, where the PDE2A enzyme is highly expressed, [13][14][15][16][17][18] were measured to assess the PD effects of compound 20 ( Fig. 8).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders

Mikami

Kawasaki

Ikeda

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.Key words phospodiesterase 2A; schizophrenia; pyrazolo[1,5-a]pyrimidine; structure-based drug design; phototoxicity; intramolecular hydrogen bond Schizophrenia is a chronic, severe, and disabling mental disorder affecting approximately 1% of the general population worldwide, [1][2][3][4] resulting in profound disruption in emotion and cognition, which has a major impact on patients' and caregivers' lives. The symptoms can typically be divided into three domains: positive (delusions and hallucinations), negative (lack of motivation and social withdrawal), and cognitive (memory, attention, and executive function) symptoms. The most recent medications commonly prescribed for schizophrenia include a new generation of antipsychotics called atypical or second-generation antipsychotics (SGAs), which function via inhibition of dopamine D2 and serotonin 5-HT 2A receptors. 5)It has been reported that these agents are reasonably effective at treating the positive symptoms of schizophrenia, but show little or no efficacy against negative and cognitive symptoms of the disease. 6) Furthermore, although generally more effective and better tolerated than typical or first-generation antipsychotics (FGAs), atypical antipsychotics also cause a variety of drug-related side effects such as sedation, weight gain, an increased risk of type II diabetes and high cholesterol, extrapyramidal symptoms, hypotension, and prolactin elevation. [7][8][9] Thus, there is a clear and high unmet medical need for a novel antipsychotic with improved efficacy and superior safety profile for the treatment of schizophrenia, especially against negative and cognitive symptoms of the disease.Owing to a growing body of preclinical research, phosphodiesterase (PDE) 2A has been recently receiving significant attention for its therapeutic potential to ...

show abstract

Section: These Efforts Resulted In the Discovery Of N-((1s)-2-hydroxymentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders

Mikami

Kawasaki

Ikeda

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

show abstract

“…Phosphodiesterase enzymes may be involved in the etiology of a number of CNS diseases, including Alzheimer's disease, schizophrenia, and affective disorders and have recently been proposed as potential targets for therapeutic intervention (Gong et al, 2004;Halene and Siegel 2007;Maxwell et al, 2004;Menniti et al, 2007;Reyes-Irisarri et al, 2007;Wong et al, 2006). In addition, PDEs may be targeted for cognitive enhancement, and inhibitors of PDEs have proven to be useful experimental tools in exploring mechanisms of learning and memory Prickaerts et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

112

View full text Add to dashboard Cite

Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [ 14 C]-iodoantipyrine and [ 14 C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.

show abstract

“…Further, there may be species differences in the expression of PDEs. Finally, PDE5 may be less suitable as a target for drug treatment, because a decrease in expression with aging and absence in the Alzheimer brain has been reported [21,22].…”

Section: Pde Localizationmentioning

confidence: 99%

PDE Inhibition and cognition enhancement

Blokland¹,

Menniti

Prickaerts

2012

Expert Opinion on Therapeutic Patents

View full text Add to dashboard Cite

Expression of the cGMP‐specific phosphodiesterases 2 and 9 in normal and Alzheimer's disease human brains

Cited by 101 publications

References 55 publications

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

PDE Inhibition and cognition enhancement

Contact Info

Product

Resources

About