The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant
Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Methods: Rapastinel was derived from a monoclonal antibody, B6...
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| Veröffentlicht in: | Current neuropharmacology 2017-01, Vol.15 (1), p.47-56 |
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| creator | Moskal, Joseph R Burgdorf, Jeffrey S Stanton, Patric K Kroes, Roger A Disterhoft, John F Burch, Ronald M Khan, M Amin |
| description | Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with
glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid
and long-lasting antidepressant properties in both animal models and in humans.
Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide
(threonine-proline-proline-threonine-amide) obtained from amino acid sequence
information obtained from sequencing one of the hypervariable regions of the light
chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined.
Results: Rapastinel was found to be a robust cognitive enhancer in a variety of
learning and memory paradigms and shows marked antidepressant-like properties in
multiple models including the forced swim (Porsolt), learned helplessness and chronic
unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its
ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with
learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs
after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover,
ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing.
Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that
may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results. |
| doi_str_mv | 10.2174/1570159x14666160321122703 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5327451</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1826669587</sourcerecordid><originalsourceid>FETCH-LOGICAL-b641t-4dfc7f325082b4c922740452bf157f421e125cabdce17bcffbe9e97db25bdac43</originalsourceid><addsrcrecordid>eNplkV-L1DAUxYso7rr6FaTiy_pQTdKkaRCEYXVXYUCQFcanmKa3na5pUpN0xn32i5vZGQf_POVAfufmnpwse4bRS4I5fYUZR5iJH5hWVYUrVBKMCeGovJed4pqzosIC3U86cUUCVyfZoxBuECKsJvxhdkIqIThD_DT7er2G_C1swLhpBBtz1-Wf1KRCHCyY_PzS-RG8uc2vll9WBS5fvM4XO2Bo84VOTJ8r2-ZLl8TyztTnCxuHFiYPISgbH2cPOmUCPDmcZ9nny3fXF--L5cerDxeLZdFUFMeCtp3mXUkYqklDtUhxKKKMNF0K0VGCAROmVdNqwLzRXdeAAMHbhrCmVZqWZ9mb_dxpbkZImI1eGTn5YVT-Vjo1yL9v7LCWvdtIVqanGE4Dzg8DvPs-Q4hyHIIGY5QFNweJa5J-W7CaJ_T5P-iNm71N8SQWNeUVr0WZKLGntHcheOiOy2Akdz3KQ4-r_3pM3qd_pjk6fxeXgJ97oElx1moMegCr4QiuY5zkdruVMHv4pgIY0FFqN0o3gZ29SdrG5JXTepI9WA9S-ThoA3IIwd7tJnfLyY0z8whJ7y7mJGSYVA-S8vIXIpLMCQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1984767893</pqid></control><display><type>article</type><title>The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Moskal, Joseph R ; Burgdorf, Jeffrey S ; Stanton, Patric K ; Kroes, Roger A ; Disterhoft, John F ; Burch, Ronald M ; Khan, M Amin</creator><creatorcontrib>Moskal, Joseph R ; Burgdorf, Jeffrey S ; Stanton, Patric K ; Kroes, Roger A ; Disterhoft, John F ; Burch, Ronald M ; Khan, M Amin</creatorcontrib><description>Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with
glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid
and long-lasting antidepressant properties in both animal models and in humans.
Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide
(threonine-proline-proline-threonine-amide) obtained from amino acid sequence
information obtained from sequencing one of the hypervariable regions of the light
chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined.
Results: Rapastinel was found to be a robust cognitive enhancer in a variety of
learning and memory paradigms and shows marked antidepressant-like properties in
multiple models including the forced swim (Porsolt), learned helplessness and chronic
unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its
ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with
learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs
after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover,
ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing.
Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that
may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.</description><identifier>ISSN: 1570-159X</identifier><identifier>EISSN: 1875-6190</identifier><identifier>DOI: 10.2174/1570159x14666160321122703</identifier><identifier>PMID: 26997507</identifier><language>eng</language><publisher>United Arab Emirates: Bentham Science Publishers Ltd</publisher><subject>Age Factors ; Amino acid sequence ; Animal models ; Animals ; Antidepressants ; Antidepressive Agents - pharmacology ; Antidepressive Agents - therapeutic use ; Cognitive ability ; Cognitive enhancement ; Dendritic spines ; Dentate gyrus ; Depression - drug therapy ; Depression - pathology ; Depression - physiopathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Exploratory Behavior - drug effects ; Glutamic acid receptors (ionotropic) ; Glycine ; Learned helplessness ; Long-term potentiation ; Long-Term Potentiation - drug effects ; Maze Learning - drug effects ; Memory ; Memory - drug effects ; Monoclonal antibodies ; N-Methyl-D-aspartic acid receptors ; Neuronal Plasticity - drug effects ; Oligopeptides - chemistry ; Oligopeptides - pharmacology ; Oligopeptides - therapeutic use ; Prefrontal cortex ; Proline ; Rats ; Receptors, N-Methyl-D-Aspartate - metabolism ; Rodents ; Swimming ; Synapses - drug effects ; Synapses - ultrastructure ; Synaptic plasticity ; Threonine ; Vocalization, Animal - drug effects</subject><ispartof>Current neuropharmacology, 2017-01, Vol.15 (1), p.47-56</ispartof><rights>Copyright Bentham Science Jan 2017</rights><rights>2017 Bentham Science Publishers 2017 Joseph R. Moskal</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b641t-4dfc7f325082b4c922740452bf157f421e125cabdce17bcffbe9e97db25bdac43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327451/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327451/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,4010,27900,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26997507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moskal, Joseph R</creatorcontrib><creatorcontrib>Burgdorf, Jeffrey S</creatorcontrib><creatorcontrib>Stanton, Patric K</creatorcontrib><creatorcontrib>Kroes, Roger A</creatorcontrib><creatorcontrib>Disterhoft, John F</creatorcontrib><creatorcontrib>Burch, Ronald M</creatorcontrib><creatorcontrib>Khan, M Amin</creatorcontrib><title>The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant</title><title>Current neuropharmacology</title><addtitle>CN</addtitle><description>Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with
glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid
and long-lasting antidepressant properties in both animal models and in humans.
Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide
(threonine-proline-proline-threonine-amide) obtained from amino acid sequence
information obtained from sequencing one of the hypervariable regions of the light
chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined.
Results: Rapastinel was found to be a robust cognitive enhancer in a variety of
learning and memory paradigms and shows marked antidepressant-like properties in
multiple models including the forced swim (Porsolt), learned helplessness and chronic
unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its
ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with
learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs
after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover,
ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing.
Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that
may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.</description><subject>Age Factors</subject><subject>Amino acid sequence</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antidepressants</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Antidepressive Agents - therapeutic use</subject><subject>Cognitive ability</subject><subject>Cognitive enhancement</subject><subject>Dendritic spines</subject><subject>Dentate gyrus</subject><subject>Depression - drug therapy</subject><subject>Depression - pathology</subject><subject>Depression - physiopathology</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical</subject><subject>Exploratory Behavior - drug effects</subject><subject>Glutamic acid receptors (ionotropic)</subject><subject>Glycine</subject><subject>Learned helplessness</subject><subject>Long-term potentiation</subject><subject>Long-Term Potentiation - drug effects</subject><subject>Maze Learning - drug effects</subject><subject>Memory</subject><subject>Memory - drug effects</subject><subject>Monoclonal antibodies</subject><subject>N-Methyl-D-aspartic acid receptors</subject><subject>Neuronal Plasticity - drug effects</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacology</subject><subject>Oligopeptides - therapeutic use</subject><subject>Prefrontal cortex</subject><subject>Proline</subject><subject>Rats</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Rodents</subject><subject>Swimming</subject><subject>Synapses - drug effects</subject><subject>Synapses - ultrastructure</subject><subject>Synaptic plasticity</subject><subject>Threonine</subject><subject>Vocalization, Animal - drug effects</subject><issn>1570-159X</issn><issn>1875-6190</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNplkV-L1DAUxYso7rr6FaTiy_pQTdKkaRCEYXVXYUCQFcanmKa3na5pUpN0xn32i5vZGQf_POVAfufmnpwse4bRS4I5fYUZR5iJH5hWVYUrVBKMCeGovJed4pqzosIC3U86cUUCVyfZoxBuECKsJvxhdkIqIThD_DT7er2G_C1swLhpBBtz1-Wf1KRCHCyY_PzS-RG8uc2vll9WBS5fvM4XO2Bo84VOTJ8r2-ZLl8TyztTnCxuHFiYPISgbH2cPOmUCPDmcZ9nny3fXF--L5cerDxeLZdFUFMeCtp3mXUkYqklDtUhxKKKMNF0K0VGCAROmVdNqwLzRXdeAAMHbhrCmVZqWZ9mb_dxpbkZImI1eGTn5YVT-Vjo1yL9v7LCWvdtIVqanGE4Dzg8DvPs-Q4hyHIIGY5QFNweJa5J-W7CaJ_T5P-iNm71N8SQWNeUVr0WZKLGntHcheOiOy2Akdz3KQ4-r_3pM3qd_pjk6fxeXgJ97oElx1moMegCr4QiuY5zkdruVMHv4pgIY0FFqN0o3gZ29SdrG5JXTepI9WA9S-ThoA3IIwd7tJnfLyY0z8whJ7y7mJGSYVA-S8vIXIpLMCQ</recordid><startdate>201701</startdate><enddate>201701</enddate><creator>Moskal, Joseph R</creator><creator>Burgdorf, Jeffrey S</creator><creator>Stanton, Patric K</creator><creator>Kroes, Roger A</creator><creator>Disterhoft, John F</creator><creator>Burch, Ronald M</creator><creator>Khan, M Amin</creator><general>Bentham Science Publishers Ltd</general><general>Benham Science Publishers</general><general>Bentham Science Publishers</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>7TK</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201701</creationdate><title>The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant</title><author>Moskal, Joseph R ; Burgdorf, Jeffrey S ; Stanton, Patric K ; Kroes, Roger A ; Disterhoft, John F ; Burch, Ronald M ; Khan, M Amin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b641t-4dfc7f325082b4c922740452bf157f421e125cabdce17bcffbe9e97db25bdac43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Age Factors</topic><topic>Amino acid sequence</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antidepressants</topic><topic>Antidepressive Agents - pharmacology</topic><topic>Antidepressive Agents - therapeutic use</topic><topic>Cognitive ability</topic><topic>Cognitive enhancement</topic><topic>Dendritic spines</topic><topic>Dentate gyrus</topic><topic>Depression - drug therapy</topic><topic>Depression - pathology</topic><topic>Depression - physiopathology</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical</topic><topic>Exploratory Behavior - drug effects</topic><topic>Glutamic acid receptors (ionotropic)</topic><topic>Glycine</topic><topic>Learned helplessness</topic><topic>Long-term potentiation</topic><topic>Long-Term Potentiation - drug effects</topic><topic>Maze Learning - drug effects</topic><topic>Memory</topic><topic>Memory - drug effects</topic><topic>Monoclonal antibodies</topic><topic>N-Methyl-D-aspartic acid receptors</topic><topic>Neuronal Plasticity - drug effects</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacology</topic><topic>Oligopeptides - therapeutic use</topic><topic>Prefrontal cortex</topic><topic>Proline</topic><topic>Rats</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Rodents</topic><topic>Swimming</topic><topic>Synapses - drug effects</topic><topic>Synapses - ultrastructure</topic><topic>Synaptic plasticity</topic><topic>Threonine</topic><topic>Vocalization, Animal - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moskal, Joseph R</creatorcontrib><creatorcontrib>Burgdorf, Jeffrey S</creatorcontrib><creatorcontrib>Stanton, Patric K</creatorcontrib><creatorcontrib>Kroes, Roger A</creatorcontrib><creatorcontrib>Disterhoft, John F</creatorcontrib><creatorcontrib>Burch, Ronald M</creatorcontrib><creatorcontrib>Khan, M Amin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Current neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moskal, Joseph R</au><au>Burgdorf, Jeffrey S</au><au>Stanton, Patric K</au><au>Kroes, Roger A</au><au>Disterhoft, John F</au><au>Burch, Ronald M</au><au>Khan, M Amin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant</atitle><jtitle>Current neuropharmacology</jtitle><addtitle>CN</addtitle><date>2017-01</date><risdate>2017</risdate><volume>15</volume><issue>1</issue><spage>47</spage><epage>56</epage><pages>47-56</pages><issn>1570-159X</issn><eissn>1875-6190</eissn><abstract>Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with
glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid
and long-lasting antidepressant properties in both animal models and in humans.
Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide
(threonine-proline-proline-threonine-amide) obtained from amino acid sequence
information obtained from sequencing one of the hypervariable regions of the light
chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined.
Results: Rapastinel was found to be a robust cognitive enhancer in a variety of
learning and memory paradigms and shows marked antidepressant-like properties in
multiple models including the forced swim (Porsolt), learned helplessness and chronic
unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its
ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with
learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs
after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover,
ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing.
Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that
may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.</abstract><cop>United Arab Emirates</cop><pub>Bentham Science Publishers Ltd</pub><pmid>26997507</pmid><doi>10.2174/1570159x14666160321122703</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Current neuropharmacology, 2017-01, Vol.15 (1), p.47-56 |
| issn | 1570-159X 1875-6190 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Age Factors Amino acid sequence Animal models Animals Antidepressants Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Cognitive ability Cognitive enhancement Dendritic spines Dentate gyrus Depression - drug therapy Depression - pathology Depression - physiopathology Disease Models, Animal Dose-Response Relationship, Drug Drug Evaluation, Preclinical Exploratory Behavior - drug effects Glutamic acid receptors (ionotropic) Glycine Learned helplessness Long-term potentiation Long-Term Potentiation - drug effects Maze Learning - drug effects Memory Memory - drug effects Monoclonal antibodies N-Methyl-D-aspartic acid receptors Neuronal Plasticity - drug effects Oligopeptides - chemistry Oligopeptides - pharmacology Oligopeptides - therapeutic use Prefrontal cortex Proline Rats Receptors, N-Methyl-D-Aspartate - metabolism Rodents Swimming Synapses - drug effects Synapses - ultrastructure Synaptic plasticity Threonine Vocalization, Animal - drug effects |
| title | The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant |
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