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

The histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H(3)R and H(4)R 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 H(3)R/H(4)R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01 series) molecules were synthesized and evaluated as H(3)R and H(4)R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H(3)R (pK(i) 6.40), while the chlorinated compound LINS01007 has moderate affinity for H(4)R (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.