Amino substituted analogs of 1-phenyl-3-phenylimino-2-indolones with potent galanin Gal3 receptor binding affinity and improved solubility

Determining receptor–ligand interaction of human galanin receptor type 3

“…Early studies of the galaninergic system, including mutagenesis studies, mainly focused on the GalR1 subtype, wherefore GalR1 is the most well characterized entity of the three receptors. However, since the introduction of several subtype preferential ligands (Liu et al, 2001;Sollenberg et al, 2006;Konkel et al, 2006;Runesson et al, 2009a;Robertson et al, 2010) have the other receptor subtypes gained increased interest. To further delineate the galaninergic system, highly selective tools are needed.…”

“…SNAP398299 was a kind gift from Lundbeck Research U.S.A., Inc. Paramus, NJ, U.S.A. (Konkel et al, 2006).…”

“…Therefore a five amino acid long galanin fragment (WTLNS), starting from the second position, was chosen for the docking studies. The SNAP398299 synthetic compound was also used (Konkel et al, 2006). Molecular docking of the ligands into the receptor structure was done using Glide.…”

“…So far, GalR1 and GalR2 are the most studied of the three receptors, mainly due to availability of transgenic animals and stably transfected cell lines, and a broader distribution pattern in the nervous system. However, since Konkel et al presented 1,phenyl]-3- [[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (hereafter referred to as SNAP398299) (Konkel et al, 2006), a non-peptidergic antagonist towards GalR3, this receptor has gained increased interest, as SNAP398299 has been successfully used as an antidepressant in rodent models of depression (Swanson et al, 2005) and ligands targeting GalR3 are promising drug candidates.…”

“…Here, we have performed sitedirected mutagenesis of hGalR3 to elucidate the importance of specific residues corresponding to residues found in GalR1 and GalR2, to be vital for galanin binding. Further, characterization of the ligand binding site was performed by utilizing the subtype selective ligand SNAP398299 (Konkel et al, 2006). Additionally, in silico docking models of the wildtype (wt) hGalR3 and L-Ala-mutated hGalR3 was done in attempt to further explain the binding results.…”