Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice
Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issu...
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| Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 2018-10, Vol.43 (11), p.2299-2309 |
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| creator | Zhang, Chong Xu, Ying Chowdhary, Anirudh Fox, 3rd, David Gurney, Mark E Zhang, Han-Ting Auerbach, Benjamin D Salvi, Richard J Yang, Mingxin Li, Gaowen O'Donnell, James M |
| description | Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors. |
| doi_str_mv | 10.1038/s41386-018-0178-6 |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.</description><identifier>ISSN: 0893-133X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1038/s41386-018-0178-6</identifier><identifier>PMID: 30131563</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Allosteric properties ; Allosteric Regulation - drug effects ; Allosteric Regulation - physiology ; Animal cognition ; Animals ; Brain ; Brain-derived neurotrophic factor ; Crystallography, X-Ray ; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism ; Dose-Response Relationship, Drug ; Drug development ; Enzymes ; Gene expression ; Humans ; Inhibitors ; Insects ; Kinases ; Laboratory animals ; Maze Learning - drug effects ; Maze Learning - physiology ; Memory ; Memory - drug effects ; Memory - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Monkeys & apes ; Mutation ; Nausea ; Neuroplasticity ; Pharmaceutical sciences ; Phosphodiesterase ; Phosphodiesterase 4 Inhibitors - chemistry ; Phosphodiesterase 4 Inhibitors - metabolism ; Phosphodiesterase 4 Inhibitors - pharmacology ; Phosphorylation ; Protein Binding - physiology ; Proteins ; Scopolamine ; Side effects ; Stem cells ; Vomiting</subject><ispartof>Neuropsychopharmacology (New York, N.Y.), 2018-10, Vol.43 (11), p.2299-2309</ispartof><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice</title><title>Neuropsychopharmacology (New York, N.Y.)</title><addtitle>Neuropsychopharmacology</addtitle><description>Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.</description><subject>Allosteric properties</subject><subject>Allosteric Regulation - drug effects</subject><subject>Allosteric Regulation - physiology</subject><subject>Animal cognition</subject><subject>Animals</subject><subject>Brain</subject><subject>Brain-derived neurotrophic factor</subject><subject>Crystallography, X-Ray</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug development</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Insects</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Maze Learning - drug effects</subject><subject>Maze Learning - physiology</subject><subject>Memory</subject><subject>Memory - drug effects</subject><subject>Memory - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Monkeys & apes</subject><subject>Mutation</subject><subject>Nausea</subject><subject>Neuroplasticity</subject><subject>Pharmaceutical sciences</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase 4 Inhibitors - chemistry</subject><subject>Phosphodiesterase 4 Inhibitors - metabolism</subject><subject>Phosphodiesterase 4 Inhibitors - pharmacology</subject><subject>Phosphorylation</subject><subject>Protein Binding - physiology</subject><subject>Proteins</subject><subject>Scopolamine</subject><subject>Side effects</subject><subject>Stem cells</subject><subject>Vomiting</subject><issn>0893-133X</issn><issn>1740-634X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdUctuFDEQtBCILIEP4IIsuHDIgD1-jH2JBOEphccBpNwsr6edcTRjL_ZM0PL1eLQhAg6tPnRVd1cVQo8peUEJUy8Lp0zJhlBVq1ONvIM2tOOkkYxf3EUbojRrKGMXR-hBKVeEUNFJdR8dMUIZFZJt0PUnmFLeY4iDjS7ESwzeg5sLTh6__vqZ8q4jJ9hGbMcxlRlycDjEIWzDnPIK2g2p1OoDrFNboOFvTioE_wxj38z7HVR2j4dlsjH8gh5PwcFDdM_bscCjm36Mvr97--3sQ3P-5f3Hs1fnjeOCz43Wrdt6zpXuCWP1L1X1Qtd7J6wFUWV4KVgL7VYT1QpKhQDHts51nveeanaMTg97d8t2gt5BnLMdzS6Hyea9STaYfycxDOYyXRtJmVCS1AVPDwuq9mCKCzO4waUYq0eGcq072VbQ85srOf1Yqg9mCsXBONoIaSmmJZoqKpTgFfrsP-hVWnKsHpiWklaTlnXrVXpAuZxKyeBvP6bErNGbQ_SmRm_W6I2snCd_S71l_Mma_QYfJKnf</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>Zhang, Chong</creator><creator>Xu, Ying</creator><creator>Chowdhary, Anirudh</creator><creator>Fox, 3rd, David</creator><creator>Gurney, Mark E</creator><creator>Zhang, Han-Ting</creator><creator>Auerbach, Benjamin D</creator><creator>Salvi, Richard J</creator><creator>Yang, Mingxin</creator><creator>Li, Gaowen</creator><creator>O'Donnell, James M</creator><general>Nature Publishing Group</general><general>Nature</general><general>Springer International Publishing</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7966-6910</orcidid><orcidid>https://orcid.org/0000-0003-4901-3083</orcidid><orcidid>https://orcid.org/0000-0002-8994-7588</orcidid><orcidid>https://orcid.org/0000000179666910</orcidid><orcidid>https://orcid.org/0000000349013083</orcidid><orcidid>https://orcid.org/0000000289947588</orcidid></search><sort><creationdate>20181001</creationdate><title>Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice</title><author>Zhang, Chong ; Xu, Ying ; Chowdhary, Anirudh ; Fox, 3rd, David ; Gurney, Mark E ; Zhang, Han-Ting ; Auerbach, Benjamin D ; Salvi, Richard J ; Yang, Mingxin ; Li, Gaowen ; O'Donnell, James M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-992cbf4489d033fec8386e7dfc5aae5301f6532e2b908251155ec3bcc7f4df193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Allosteric properties</topic><topic>Allosteric Regulation - drug effects</topic><topic>Allosteric Regulation - physiology</topic><topic>Animal cognition</topic><topic>Animals</topic><topic>Brain</topic><topic>Brain-derived neurotrophic factor</topic><topic>Crystallography, X-Ray</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug development</topic><topic>Enzymes</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Insects</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Maze Learning - drug effects</topic><topic>Maze Learning - physiology</topic><topic>Memory</topic><topic>Memory - drug effects</topic><topic>Memory - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Monkeys & apes</topic><topic>Mutation</topic><topic>Nausea</topic><topic>Neuroplasticity</topic><topic>Pharmaceutical sciences</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase 4 Inhibitors - chemistry</topic><topic>Phosphodiesterase 4 Inhibitors - metabolism</topic><topic>Phosphodiesterase 4 Inhibitors - pharmacology</topic><topic>Phosphorylation</topic><topic>Protein Binding - physiology</topic><topic>Proteins</topic><topic>Scopolamine</topic><topic>Side effects</topic><topic>Stem cells</topic><topic>Vomiting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Chong</creatorcontrib><creatorcontrib>Xu, Ying</creatorcontrib><creatorcontrib>Chowdhary, Anirudh</creatorcontrib><creatorcontrib>Fox, 3rd, David</creatorcontrib><creatorcontrib>Gurney, Mark E</creatorcontrib><creatorcontrib>Zhang, Han-Ting</creatorcontrib><creatorcontrib>Auerbach, Benjamin D</creatorcontrib><creatorcontrib>Salvi, Richard J</creatorcontrib><creatorcontrib>Yang, Mingxin</creatorcontrib><creatorcontrib>Li, Gaowen</creatorcontrib><creatorcontrib>O'Donnell, James M</creatorcontrib><creatorcontrib>Argonne National Lab. 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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice</atitle><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle><addtitle>Neuropsychopharmacology</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>43</volume><issue>11</issue><spage>2299</spage><epage>2309</epage><pages>2299-2309</pages><issn>0893-133X</issn><eissn>1740-634X</eissn><abstract>Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. 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| source | MEDLINE; Springer Nature - Complete Springer Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Allosteric properties Allosteric Regulation - drug effects Allosteric Regulation - physiology Animal cognition Animals Brain Brain-derived neurotrophic factor Crystallography, X-Ray Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism Dose-Response Relationship, Drug Drug development Enzymes Gene expression Humans Inhibitors Insects Kinases Laboratory animals Maze Learning - drug effects Maze Learning - physiology Memory Memory - drug effects Memory - physiology Mice Mice, Inbred C57BL Mice, Transgenic Monkeys & apes Mutation Nausea Neuroplasticity Pharmaceutical sciences Phosphodiesterase Phosphodiesterase 4 Inhibitors - chemistry Phosphodiesterase 4 Inhibitors - metabolism Phosphodiesterase 4 Inhibitors - pharmacology Phosphorylation Protein Binding - physiology Proteins Scopolamine Side effects Stem cells Vomiting |
| title | Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice |
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