Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder
Treatment-resistant depression responds quickly to ketamine. As an -methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the ( )-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Ad...
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| Veröffentlicht in: | Journal of medicinal chemistry 2025-01, Vol.68 (2), p.944 |
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| creator | Faustino Martins, Allana Cristina Badenoch, Bretton da Silva Gomes, Roberto |
| description | Treatment-resistant depression responds quickly to ketamine. As an
-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (
)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (
)-enantiomer for medical usage. (2
,6
)-Hydroxynorketamine (HNK) inhibits mGlu2, linked to a Gi, in presynaptic glutamatergic neurons, increasing brain-derived neurotrophic factor (BDNF) release, which autocrinely activates Tropomyosin receptor kinase B (TrkB) and promotes synaptogenesis. Ketamine, originally an anesthetic, has garnered attention for its many pharmacological effects, including its potential as a rapid-acting antidepressant and recreational use. In this Perspective, we explore the synthesis, pharmacology, metabolism, and effects of ketamine and its metabolites in animal and human studies to explain the difference in the biological activity between the enantiomers. |
| doi_str_mv | 10.1021/acs.jmedchem.4c02467 |
| format | Article |
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-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (
)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (
)-enantiomer for medical usage. (2
,6
)-Hydroxynorketamine (HNK) inhibits mGlu2, linked to a Gi, in presynaptic glutamatergic neurons, increasing brain-derived neurotrophic factor (BDNF) release, which autocrinely activates Tropomyosin receptor kinase B (TrkB) and promotes synaptogenesis. Ketamine, originally an anesthetic, has garnered attention for its many pharmacological effects, including its potential as a rapid-acting antidepressant and recreational use. In this Perspective, we explore the synthesis, pharmacology, metabolism, and effects of ketamine and its metabolites in animal and human studies to explain the difference in the biological activity between the enantiomers.</description><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c02467</identifier><identifier>PMID: 39757458</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antidepressive Agents - chemistry ; Antidepressive Agents - pharmacology ; Antidepressive Agents - therapeutic use ; Depressive Disorder - drug therapy ; Humans ; Ketamine - pharmacology ; Ketamine - therapeutic use ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate - metabolism ; Stereoisomerism</subject><ispartof>Journal of medicinal chemistry, 2025-01, Vol.68 (2), p.944</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-8075-9716 ; 0000-0001-5647-2187</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39757458$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Faustino Martins, Allana Cristina</creatorcontrib><creatorcontrib>Badenoch, Bretton</creatorcontrib><creatorcontrib>da Silva Gomes, Roberto</creatorcontrib><title>Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Treatment-resistant depression responds quickly to ketamine. As an
-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (
)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (
)-enantiomer for medical usage. (2
,6
)-Hydroxynorketamine (HNK) inhibits mGlu2, linked to a Gi, in presynaptic glutamatergic neurons, increasing brain-derived neurotrophic factor (BDNF) release, which autocrinely activates Tropomyosin receptor kinase B (TrkB) and promotes synaptogenesis. Ketamine, originally an anesthetic, has garnered attention for its many pharmacological effects, including its potential as a rapid-acting antidepressant and recreational use. In this Perspective, we explore the synthesis, pharmacology, metabolism, and effects of ketamine and its metabolites in animal and human studies to explain the difference in the biological activity between the enantiomers.</description><subject>Animals</subject><subject>Antidepressive Agents - chemistry</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Antidepressive Agents - therapeutic use</subject><subject>Depressive Disorder - drug therapy</subject><subject>Humans</subject><subject>Ketamine - pharmacology</subject><subject>Ketamine - therapeutic use</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Stereoisomerism</subject><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkMtOwzAURC0EoqXwBwhlySbF8TNeohZKRQWbso6unRuaqnlgOwj-niIKYjUjzdEsDiGXGZ1mlGU34MJ022DpNthMhaNMKH1ExplkNBU5Fcf_-oichbCllPKM8VMy4kZLLWQ-Ji_LNtSvmxiSqvNJ3GDyhB8xWWCLHmLdtUlXJY8Yoalb_GPWHiE22MbvdY69xxDqd0zmdeh8if6cnFSwC3hxyAlZ39-tZw_p6nmxnN2u0l6qPAWlJGo0WDJlnEPFKeZMWKfB5qVmBi1UzoK2VFlglZUIrHTOQMUZGOQTcv1z2_vubcAQi6YODnc7aLEbQsEzmeVaUyP26NUBHexeWtH7ugH_Wfya4F8SF2Tp</recordid><startdate>20250123</startdate><enddate>20250123</enddate><creator>Faustino Martins, Allana Cristina</creator><creator>Badenoch, Bretton</creator><creator>da Silva Gomes, Roberto</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8075-9716</orcidid><orcidid>https://orcid.org/0000-0001-5647-2187</orcidid></search><sort><creationdate>20250123</creationdate><title>Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder</title><author>Faustino Martins, Allana Cristina ; Badenoch, Bretton ; da Silva Gomes, Roberto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p568-a665e7e9ed269cce630e824bc7ab8d729ebafcba7b06ba2fb5ea2dcc9af32a9e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Antidepressive Agents - chemistry</topic><topic>Antidepressive Agents - pharmacology</topic><topic>Antidepressive Agents - therapeutic use</topic><topic>Depressive Disorder - drug therapy</topic><topic>Humans</topic><topic>Ketamine - pharmacology</topic><topic>Ketamine - therapeutic use</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Stereoisomerism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Faustino Martins, Allana Cristina</creatorcontrib><creatorcontrib>Badenoch, Bretton</creatorcontrib><creatorcontrib>da Silva Gomes, Roberto</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Faustino Martins, Allana Cristina</au><au>Badenoch, Bretton</au><au>da Silva Gomes, Roberto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2025-01-23</date><risdate>2025</risdate><volume>68</volume><issue>2</issue><spage>944</spage><pages>944-</pages><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Treatment-resistant depression responds quickly to ketamine. As an
-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (
)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (
)-enantiomer for medical usage. (2
,6
)-Hydroxynorketamine (HNK) inhibits mGlu2, linked to a Gi, in presynaptic glutamatergic neurons, increasing brain-derived neurotrophic factor (BDNF) release, which autocrinely activates Tropomyosin receptor kinase B (TrkB) and promotes synaptogenesis. Ketamine, originally an anesthetic, has garnered attention for its many pharmacological effects, including its potential as a rapid-acting antidepressant and recreational use. In this Perspective, we explore the synthesis, pharmacology, metabolism, and effects of ketamine and its metabolites in animal and human studies to explain the difference in the biological activity between the enantiomers.</abstract><cop>United States</cop><pmid>39757458</pmid><doi>10.1021/acs.jmedchem.4c02467</doi><orcidid>https://orcid.org/0000-0002-8075-9716</orcidid><orcidid>https://orcid.org/0000-0001-5647-2187</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2025-01, Vol.68 (2), p.944 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Antidepressive Agents - chemistry Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Depressive Disorder - drug therapy Humans Ketamine - pharmacology Ketamine - therapeutic use Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - metabolism Stereoisomerism |
| title | Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder |
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