Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists

The human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the 5-HT2A and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethyl...

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Detalhes bibliográficos
Autores: Yempala, Thirumal, Brea Floriani, José Manuel, Loza García, María Isabel, Matthies, Douglas J., Zapata-Torres, Gerald, Cassels, Bruce K.
Tipo de documento: artigo
Data de publicação:2020
País:España
Recursos:Universidad de Santiago de Compostela (USC)
Repositório:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
Idioma:inglês
OAI Identifier:oai:minerva.usc.gal:10347/45557
Acesso em linha:https://hdl.handle.net/10347/45557
Access Level:Acceso aberto
Palavra-chave:Agonists
Aromatic compounds
Crystal structure
Noncovalent interactions
Receptors
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spelling Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor AgonistsYempala, ThirumalBrea Floriani, José ManuelLoza García, María IsabelMatthies, Douglas J.Zapata-Torres, GeraldCassels, Bruce K.AgonistsAromatic compoundsCrystal structureNoncovalent interactionsReceptorsThe human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the 5-HT2A and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethylamine analogs in which the benzene ring is replaced by a bulky dibenzo[b,d]furan moiety and found a couple with >70-fold 5-HT2C selectivity. Molecular docking studies of the most potent compound (5) at both receptor subtypes revealed the likely structural basis of its selectivity. Although in both cases, some crucial interactions are conserved, the change of the Ala2225.46 residue in the 5-HT2C receptor to the larger Ser2425.46 in the 5-HT 2A subtype, which is the only structural difference between the orthosteric binding pockets of both receptors, weakens a π−π stacking interaction between the dibenzofuran moiety and the important Phe6.52 residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser5.43 , explaining the selectivity of compound 5 for the 5-HT 2C receptor. We believe that this effect of the residue at position 5.46 merits further exploration in the search for selective 5-HT 2C receptor agonists that are of considerable interest in the treatment of schizophreniaACSUniversidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía FarmacéuticaUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)20202020-01-2720202020-01-27journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/45557reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostelainstname:Universidad de Santiago de Compostela (USC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Copyright © 2020 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:minerva.usc.gal:10347/455572026-06-15T12:47:27Z
dc.title.none.fl_str_mv Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
title Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
spellingShingle Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
Yempala, Thirumal
Agonists
Aromatic compounds
Crystal structure
Noncovalent interactions
Receptors
title_short Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
title_full Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
title_fullStr Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
title_full_unstemmed Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
title_sort Dibenzofuranylethylamines as 5-HT<sub>2A/2C</sub> Receptor Agonists
dc.creator.none.fl_str_mv Yempala, Thirumal
Brea Floriani, José Manuel
Loza García, María Isabel
Matthies, Douglas J.
Zapata-Torres, Gerald
Cassels, Bruce K.
author Yempala, Thirumal
author_facet Yempala, Thirumal
Brea Floriani, José Manuel
Loza García, María Isabel
Matthies, Douglas J.
Zapata-Torres, Gerald
Cassels, Bruce K.
author_role author
author2 Brea Floriani, José Manuel
Loza García, María Isabel
Matthies, Douglas J.
Zapata-Torres, Gerald
Cassels, Bruce K.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica
Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
dc.subject.none.fl_str_mv Agonists
Aromatic compounds
Crystal structure
Noncovalent interactions
Receptors
topic Agonists
Aromatic compounds
Crystal structure
Noncovalent interactions
Receptors
description The human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the 5-HT2A and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethylamine analogs in which the benzene ring is replaced by a bulky dibenzo[b,d]furan moiety and found a couple with >70-fold 5-HT2C selectivity. Molecular docking studies of the most potent compound (5) at both receptor subtypes revealed the likely structural basis of its selectivity. Although in both cases, some crucial interactions are conserved, the change of the Ala2225.46 residue in the 5-HT2C receptor to the larger Ser2425.46 in the 5-HT 2A subtype, which is the only structural difference between the orthosteric binding pockets of both receptors, weakens a π−π stacking interaction between the dibenzofuran moiety and the important Phe6.52 residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser5.43 , explaining the selectivity of compound 5 for the 5-HT 2C receptor. We believe that this effect of the residue at position 5.46 merits further exploration in the search for selective 5-HT 2C receptor agonists that are of considerable interest in the treatment of schizophrenia
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-27
2020
2020-01-27
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10347/45557
url https://hdl.handle.net/10347/45557
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv ACS
publisher.none.fl_str_mv ACS
dc.source.none.fl_str_mv reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
instname:Universidad de Santiago de Compostela (USC)
instname_str Universidad de Santiago de Compostela (USC)
reponame_str Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
collection Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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