The lead compound 1 and derivative 2 were previously characterize

The lead compound 1 and derivative 2 were previously characterized as anti-estrogens (Masatoshi et al., 1993; von Angerer et al., 1984, 1987, 1990). Compound 3 is a new compound. Compound 4 was obtained in Friedel–Crafts acylation of indole as previously described (Guchhait et al., 2011).

Derivative 5 is a new compound and was obtained in alkylation of 4 with 4-chlorobenzyl chloride. Compound 6 was obtained by cyclization of monophenylhydrazone of 1,3-cyclohexadione (obtained from phenylhydrazine and this website 1,3-cyclohexadione) in PPA and was characterized previously (Rodriguez et al., 1989). Compound 7 is a new compound and was obtained by alkylation of 6 with 4-chlorobenzyl chloride. Fig. 2 Scheme of reactions Pharmacology BI 6727 cost Compounds 3 and 5–7 were tested

for their affinity to GluK2 receptors as described previously (Kaczor et al., 2012; 2014). The IC50 values for the compounds being investigated are listed in Table 1. The investigations with the 3H-kainate binding assay showed no inhibition, which makes it possible to conclude that the antagonism for compounds 3 and 5 is of the non-competitive type. Table 1 Pharmacological activity of novel ligands Compound GluK2 IC50, μM 1 0.7 3 12.0 5 1.7 6 100 7 22 % at 100 μm Structural and electronic parameters of novel ligands In order to address the structure–activity relationship observed, structural and electronic parameters were calculated for compounds 1, Lepirudin 3, 5, 6, and 7. The data are presented in Tables 2 NVP-BGJ398 cell line and 3. The data shown in Table 2 show that the lack of activity of compound 6 may be explained by the fact that the molecular volume is too low and the

dipole moment too high. The significant difference between the HOMO and LUMO values (Table 3) indicates that the compounds are nucleophilic and may participate as acceptors (through oxygen atoms) in hydrogen bonds with the binding pocket residues; this is in agreement with our earlier studies (Kaczor et al., 2012). Moreover, the novel ligands have more favorable lipophilicity values in comparison to the previous series, with the exception of compound 5 (Kaczor et al., 2012). Table 2 Structural parameters of novel ligands Compound Surface, Å2 Ovality Volume, Å3 Dipole moment, D 1 557.80 1.6637 324.86 3.97 3 485.2 1.5612 232.00 3.12 5 642.50 1.7163 335.30 3.89 6 379.00 1.4094 171.10 4.92 7 528.50 1.6128 274.00 3.95 Table 3 Electronic and physicochemical parameters of novel ligands Compound EHOMO, eV ELUMO, eV Lipophilicity 1 −8.03 0.04 4.94 3 −8.10 −0.33 4.65 5 −8.66 −0.52 6.44 6 −8.59 −0.14 2.51 7 −8.57 −0.39 4.96 Ligand-receptor interactions The binding site for non-competitive GluK2 receptor antagonists was identified in the receptor transduction domain, i.e., in the domain which connects the ligand-binding domain and the transmembrane domain (Fig. 3). This assumption was made on the basis of studies by (Balannik et al.

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