Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H-3 and H-4 Receptors with Anti-inflammatory Potential

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dc.citation.volume8
dc.contributor.authorCorrea, Michelle F. [UNIFESP]
dc.contributor.authorBarbosa, Alefe J. R. [UNIFESP]
dc.contributor.authorTeixeira, Larissa B.
dc.contributor.authorDuarte, Diego A.
dc.contributor.authorSimoes, Sarah C.
dc.contributor.authorParreiras-e-Silva, Lucas T.
dc.contributor.authorBalbino, Aleksandro M. [UNIFESP]
dc.contributor.authorLandgraf, Richardt G. [UNIFESP]
dc.contributor.authorBouvier, Michel
dc.contributor.authorCosta-Neto, Claudio M.
dc.contributor.authorFernandes, Joao P. S. [UNIFESP]
dc.coverageLausanne
dc.date.accessioned2020-09-01T13:21:17Z
dc.date.available2020-09-01T13:21:17Z
dc.date.issued2017
dc.description.abstractThe histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson's, and Alzheimer's diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl) methyl] piperazine (LINS01 series) molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pK(i) 6.40), while the chlorinated compound LINS01007 has moderate affinity for H4R (pK(i) 6.06). In addition, BRET assays to assess the functional activity of G(i)1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg) than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.en
dc.description.affiliationUniv Fed Sao Paulo, Dept Ciencias Farmaceut, Diadema, Brazil
dc.description.affiliationUniv Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto, Brazil
dc.description.affiliationUniv Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ, Canada
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Ciencias Farmaceut, Diadema, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFAPESP
dc.description.sponsorshipCNPq
dc.description.sponsorshipCAPES
dc.description.sponsorshipCanadian Institute for Health Research
dc.description.sponsorshipIDFAPESP: 2013/20479-9
dc.description.sponsorshipIDFAPESP: 2016/25028-3
dc.description.sponsorshipIDFAPESP: 2017/02042-3
dc.description.sponsorshipIDFAPESP: 2012/20148-0
dc.description.sponsorshipIDFAPESP: 2016/23139-2
dc.description.sponsorshipIDCNPq: 455411/2014-0
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.3389/fphar.2017.00825
dc.identifier.citationFrontiers In Pharmacology. Lausanne, v. 8, p. -, 2017.
dc.identifier.doi10.3389/fphar.2017.00825
dc.identifier.fileWOS000415041800005.pdf
dc.identifier.issn1663-9812
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/58174
dc.identifier.wosWOS:000415041800005
dc.language.isoeng
dc.publisherFrontiers Media Sa
dc.relation.ispartofFrontiers In Pharmacology
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectH3R antagonistsen
dc.subjectH4R antagonistsen
dc.subjecthistamine receptorsen
dc.subjectdihydrobenzofuranen
dc.subjectSARen
dc.subjectanti-inflammatory activityen
dc.subjectasthmaen
dc.titlePharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H-3 and H-4 Receptors with Anti-inflammatory Potentialen
dc.typeinfo:eu-repo/semantics/article
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