Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II)
In this paper we report the investigation of C-3 and β-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the β-acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affini...
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| Veröffentlicht in: | European journal of medicinal chemistry 2015-01, Vol.90, p.822-833 |
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| container_title | European journal of medicinal chemistry |
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| creator | Ettaoussi, Mohamed Pérès, Basile Errazani, Aïcha Boutin, Jean A. Caignard, Daniel-Henri Delagrange, Philippe Melnyk, Patricia Berthelot, Pascal Yous, Saïd |
| description | In this paper we report the investigation of C-3 and β-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the β-acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affinities. In particular, the allyl 6b and ethyl 15a represented the more interesting compounds of this series. Furthermore, the introduction of methyl cycloalkyl groups (compounds 11a, 12a) exhibited no change in both MT2 and 5-HT2C binding affinities while a decrease of MT1 binding affinity occurred leading to an MT2 selectivity. Finally, the acetamide modulation has led to methyl thiourea 11h, with a weak MT2 selectivity.
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•New analogues of agomelatine were synthesized and tested.•Combination of β- and C-3 modulations led to compounds with good pharmacological profile.•Synthesized series conserved good melatonin binding affinities.•The allyl 7b and ethyl 16a represented the most interesting compounds of this series. |
| doi_str_mv | 10.1016/j.ejmech.2014.12.021 |
| format | Article |
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[Display omitted]
•New analogues of agomelatine were synthesized and tested.•Combination of β- and C-3 modulations led to compounds with good pharmacological profile.•Synthesized series conserved good melatonin binding affinities.•The allyl 7b and ethyl 16a represented the most interesting compounds of this series.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.12.021</identifier><identifier>PMID: 25528336</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Acetamides - chemical synthesis ; Acetamides - chemistry ; Acetamides - pharmacology ; Agomelatine ; Animals ; Chemical Sciences ; CHO Cells ; Cricetulus ; Dose-Response Relationship, Drug ; Humans ; Life Sciences ; Ligands ; Medicinal Chemistry ; Melatonin receptors ; Modulation ; Molecular Structure ; MT2-Selectivity ; Neurons and Cognition ; Receptor, Melatonin, MT1 - antagonists & inhibitors ; Receptor, Melatonin, MT1 - metabolism ; Receptor, Melatonin, MT2 - antagonists & inhibitors ; Receptor, Melatonin, MT2 - metabolism ; Receptor, Serotonin, 5-HT2C - metabolism ; Serotonin 5-HT2C receptor ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2015-01, Vol.90, p.822-833</ispartof><rights>2015 Elsevier Masson SAS</rights><rights>Copyright © 2015 Elsevier Masson SAS. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-9a81e3583bbbf932c6b5ca2e63ec267639a3470672913e3f220350af7c006d9a3</citedby><cites>FETCH-LOGICAL-c442t-9a81e3583bbbf932c6b5ca2e63ec267639a3470672913e3f220350af7c006d9a3</cites><orcidid>0000-0002-9555-3446</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523414011301$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25528336$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02060835$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Ettaoussi, Mohamed</creatorcontrib><creatorcontrib>Pérès, Basile</creatorcontrib><creatorcontrib>Errazani, Aïcha</creatorcontrib><creatorcontrib>Boutin, Jean A.</creatorcontrib><creatorcontrib>Caignard, Daniel-Henri</creatorcontrib><creatorcontrib>Delagrange, Philippe</creatorcontrib><creatorcontrib>Melnyk, Patricia</creatorcontrib><creatorcontrib>Berthelot, Pascal</creatorcontrib><creatorcontrib>Yous, Saïd</creatorcontrib><title>Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II)</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>In this paper we report the investigation of C-3 and β-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the β-acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affinities. In particular, the allyl 6b and ethyl 15a represented the more interesting compounds of this series. Furthermore, the introduction of methyl cycloalkyl groups (compounds 11a, 12a) exhibited no change in both MT2 and 5-HT2C binding affinities while a decrease of MT1 binding affinity occurred leading to an MT2 selectivity. Finally, the acetamide modulation has led to methyl thiourea 11h, with a weak MT2 selectivity.
[Display omitted]
•New analogues of agomelatine were synthesized and tested.•Combination of β- and C-3 modulations led to compounds with good pharmacological profile.•Synthesized series conserved good melatonin binding affinities.•The allyl 7b and ethyl 16a represented the most interesting compounds of this series.</description><subject>Acetamides - chemical synthesis</subject><subject>Acetamides - chemistry</subject><subject>Acetamides - pharmacology</subject><subject>Agomelatine</subject><subject>Animals</subject><subject>Chemical Sciences</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Ligands</subject><subject>Medicinal Chemistry</subject><subject>Melatonin receptors</subject><subject>Modulation</subject><subject>Molecular Structure</subject><subject>MT2-Selectivity</subject><subject>Neurons and Cognition</subject><subject>Receptor, Melatonin, MT1 - antagonists & inhibitors</subject><subject>Receptor, Melatonin, MT1 - metabolism</subject><subject>Receptor, Melatonin, MT2 - antagonists & inhibitors</subject><subject>Receptor, Melatonin, MT2 - metabolism</subject><subject>Receptor, Serotonin, 5-HT2C - metabolism</subject><subject>Serotonin 5-HT2C receptor</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMGK2zAQhkVp6Wa3fYNSdNwc7B2NLNm5FJbQNoEsPTQ9C1kebxRsy1hOINCHr1Nv99jTwD_fN0I_Y58EpAKEfjimdGzJHVIEkaUCU0Dxhi1ErotEosresgUgykShzG7YbYxHAFAa4D27QaWwkFIv2O-fl248UPSR267i_cEOrXWhCc_e2YbT2TYnO_rQ8VDz6jRFjX-eyMjrMPCWGjuGznf8_mkvHp72uPx7JtIQ5lwlmz2u-UCO-nEy4qkcLz1Ffr_dLj-wd7VtIn18mXfs17ev-_Um2f34vl0_7hKXZTgmK1sIkqqQZVnWK4lOl8pZJC3Joc61XFmZ5aBzXAlJskYEqcDWuQPQ1bS8Y8v57sE2ph98a4eLCdabzePOXDNA0FBIdRYTm82sG0KMA9WvggBzLd4czVy8uRZvBE72Vfs8a_2pbKl6lf41PQFfZoCmj549DSY6T52jyk_ljKYK_v8v_AGNqJRf</recordid><startdate>20150127</startdate><enddate>20150127</enddate><creator>Ettaoussi, Mohamed</creator><creator>Pérès, Basile</creator><creator>Errazani, Aïcha</creator><creator>Boutin, Jean A.</creator><creator>Caignard, Daniel-Henri</creator><creator>Delagrange, Philippe</creator><creator>Melnyk, Patricia</creator><creator>Berthelot, Pascal</creator><creator>Yous, Saïd</creator><general>Elsevier Masson SAS</general><general>Elsevier</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>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-9555-3446</orcidid></search><sort><creationdate>20150127</creationdate><title>Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II)</title><author>Ettaoussi, Mohamed ; Pérès, Basile ; Errazani, Aïcha ; Boutin, Jean A. ; Caignard, Daniel-Henri ; Delagrange, Philippe ; Melnyk, Patricia ; Berthelot, Pascal ; Yous, Saïd</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-9a81e3583bbbf932c6b5ca2e63ec267639a3470672913e3f220350af7c006d9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acetamides - chemical synthesis</topic><topic>Acetamides - chemistry</topic><topic>Acetamides - pharmacology</topic><topic>Agomelatine</topic><topic>Animals</topic><topic>Chemical Sciences</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Ligands</topic><topic>Medicinal Chemistry</topic><topic>Melatonin receptors</topic><topic>Modulation</topic><topic>Molecular Structure</topic><topic>MT2-Selectivity</topic><topic>Neurons and Cognition</topic><topic>Receptor, Melatonin, MT1 - antagonists & inhibitors</topic><topic>Receptor, Melatonin, MT1 - metabolism</topic><topic>Receptor, Melatonin, MT2 - antagonists & inhibitors</topic><topic>Receptor, Melatonin, MT2 - metabolism</topic><topic>Receptor, Serotonin, 5-HT2C - metabolism</topic><topic>Serotonin 5-HT2C receptor</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ettaoussi, Mohamed</creatorcontrib><creatorcontrib>Pérès, Basile</creatorcontrib><creatorcontrib>Errazani, Aïcha</creatorcontrib><creatorcontrib>Boutin, Jean A.</creatorcontrib><creatorcontrib>Caignard, Daniel-Henri</creatorcontrib><creatorcontrib>Delagrange, Philippe</creatorcontrib><creatorcontrib>Melnyk, Patricia</creatorcontrib><creatorcontrib>Berthelot, Pascal</creatorcontrib><creatorcontrib>Yous, Saïd</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ettaoussi, Mohamed</au><au>Pérès, Basile</au><au>Errazani, Aïcha</au><au>Boutin, Jean A.</au><au>Caignard, Daniel-Henri</au><au>Delagrange, Philippe</au><au>Melnyk, Patricia</au><au>Berthelot, Pascal</au><au>Yous, Saïd</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II)</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2015-01-27</date><risdate>2015</risdate><volume>90</volume><spage>822</spage><epage>833</epage><pages>822-833</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>In this paper we report the investigation of C-3 and β-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the β-acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affinities. In particular, the allyl 6b and ethyl 15a represented the more interesting compounds of this series. Furthermore, the introduction of methyl cycloalkyl groups (compounds 11a, 12a) exhibited no change in both MT2 and 5-HT2C binding affinities while a decrease of MT1 binding affinity occurred leading to an MT2 selectivity. Finally, the acetamide modulation has led to methyl thiourea 11h, with a weak MT2 selectivity.
[Display omitted]
•New analogues of agomelatine were synthesized and tested.•Combination of β- and C-3 modulations led to compounds with good pharmacological profile.•Synthesized series conserved good melatonin binding affinities.•The allyl 7b and ethyl 16a represented the most interesting compounds of this series.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>25528336</pmid><doi>10.1016/j.ejmech.2014.12.021</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-9555-3446</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of medicinal chemistry, 2015-01, Vol.90, p.822-833 |
| issn | 0223-5234 1768-3254 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Acetamides - chemical synthesis Acetamides - chemistry Acetamides - pharmacology Agomelatine Animals Chemical Sciences CHO Cells Cricetulus Dose-Response Relationship, Drug Humans Life Sciences Ligands Medicinal Chemistry Melatonin receptors Modulation Molecular Structure MT2-Selectivity Neurons and Cognition Receptor, Melatonin, MT1 - antagonists & inhibitors Receptor, Melatonin, MT1 - metabolism Receptor, Melatonin, MT2 - antagonists & inhibitors Receptor, Melatonin, MT2 - metabolism Receptor, Serotonin, 5-HT2C - metabolism Serotonin 5-HT2C receptor Structure-Activity Relationship |
| title | Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II) |
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