Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis).
Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat di...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4106781?pdf=render |
| _version_ | 1819209680225828864 |
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| author | Jane S Sutcliffe Vahri Beaumont James M Watson Chang Sing Chew Maria Beconi Daniel M Hutcheson Celia Dominguez Ignacio Munoz-Sanjuan |
| author_facet | Jane S Sutcliffe Vahri Beaumont James M Watson Chang Sing Chew Maria Beconi Daniel M Hutcheson Celia Dominguez Ignacio Munoz-Sanjuan |
| author_sort | Jane S Sutcliffe |
| collection | DOAJ |
| description | Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline. |
| first_indexed | 2024-12-23T05:59:08Z |
| format | Article |
| id | doaj.art-9a4e3bbf7a6042d28ac2f2f8351e4140 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T05:59:08Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9a4e3bbf7a6042d28ac2f2f8351e41402022-12-21T17:57:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10244910.1371/journal.pone.0102449Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis).Jane S SutcliffeVahri BeaumontJames M WatsonChang Sing ChewMaria BeconiDaniel M HutchesonCelia DominguezIgnacio Munoz-SanjuanCyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.http://europepmc.org/articles/PMC4106781?pdf=render |
| spellingShingle | Jane S Sutcliffe Vahri Beaumont James M Watson Chang Sing Chew Maria Beconi Daniel M Hutcheson Celia Dominguez Ignacio Munoz-Sanjuan Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). PLoS ONE |
| title | Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). |
| title_full | Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). |
| title_fullStr | Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). |
| title_full_unstemmed | Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). |
| title_short | Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). |
| title_sort | efficacy of selective pde4d negative allosteric modulators in the object retrieval task in female cynomolgus monkeys macaca fascicularis |
| url | http://europepmc.org/articles/PMC4106781?pdf=render |
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