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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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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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]
Total Authors: 11
[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
Total Affiliations: 3
Document type: Journal article
Web of Science Citations: 7

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)

FAPESP's process: 16/23139-2 - Synthesis and biological evaluation of the LINS01 series as procognitive agents: a multitarget approach
Grantee:Michelle Fidelis Corrêa
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 13/20479-9 - Synthesis and evaluation of compounds potentially ligands of H4 receptors
Grantee:João Paulo dos Santos Fernandes
Support type: Regular Research Grants
FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
Grantee:João Paulo dos Santos Fernandes
Support type: Regular Research Grants
FAPESP's process: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
Grantee:Claudio Miguel da Costa Neto
Support type: Research Projects - Thematic Grants
FAPESP's process: 17/02042-3 - Molecular mechanisms involved in lung inflammatory response induced by LPS in the F2 generation of low birth weight rats
Grantee:Richardt Gama Landgraf
Support type: Regular Research Grants