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

Autor(es):Mostrar menos -

Correa, Michelle F. ^[1] ; Barbosa, Alefe J. R. ^[1] ; Teixeira, Larissa B. ^[2] ; Duarte, Diego A. ^[2] ; Simoes, Sarah C. ^[2] ; Parreiras-e-Silva, Lucas T. ^[2] ; Balbino, Aleksandro M. ^[1] ; Landgraf, Richardt G. ^[1] ; Bouvier, Michel ^[3] ; Costa-Neto, Claudio M. ^[2] ; Fernandes, Joao P. S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Ciencias Farmaceut, Diadema - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto - Brazil

^[3] Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ - Canada

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHARMACOLOGY; v. 8, NOV 14 2017.
• Citações Web of Science: 7

Resumo

The 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. (AU)

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• Beneficiário: Claudio Miguel da Costa Neto
• Modalidade de apoio: Auxílio à Pesquisa - Temático
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• Modalidade de apoio: Auxílio à Pesquisa - Regular
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• Modalidade de apoio: Bolsas no Brasil - Doutorado
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• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
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• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular