Identification of important pharmacophores in the galanin receptor subtypes

The neuropeptide galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. Galanin and galanin receptors (GalR1-3) show a widespread distribution throughout nervous systems where galanin co-localizes with several neuropeptides and/or classical neurotransmitters. Regionally specific expression of the galanin receptors suggests different physiological roles, a feature which mostly remains unexplored due to the lack of stable, selective and potent ligands acting on the galanin receptor subtypes. In order to design novel galanin receptor ligands with enhanced subtype selectivity we are aiming at determining the molecular interaction between the galanin peptide and the galanin receptor subtypes. By introducing site directed mutations to the extracellular loops and the external parts of the transmembrane domains in the galanin receptor subtypes we will characterize areas and single amino acids with significant importance for ligand binding to this receptor.