Dihydrobenzofuranyl-phenylpiperazines as vasodilating agents: synthesis and evalua...
| Full text | |
| Author(s): Show less - |
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
|
| Affiliation: | [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 |
| Source: | FRONTIERS IN PHARMACOLOGY; v. 8, NOV 14 2017. |
| Web of Science Citations: | 7 |
| Abstract | |
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 |