The quest for a GPCR selective ligand – a bottleneck

The family of GPCR’s has for long served as the most common pharmaceutical drug target. Even so, some receptors have failed to show any interactions when exposed to big screenings libraries in the past and consequently they also lack potent small molecules acting as ligands on these different receptors. Three of these receptors are the so called galanin receptors (GalR). Galanin is a neuroendocrine peptide that is widely distributed in both the central and peripheral nervous systems as well as in the endocrine system. The galanin peptide 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. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this peptide family. The regionally specific expression of the galanin receptors (GalR1-3) suggests different physiological roles, a feature which mostly remains unexplored due to the lack of selective ligands acting on the galanin receptor subtypes. The first introduced receptor subtype specific ligand in the field was galanin(2-11) as a GalR2 selective ligand, which was an important advance in the galanin field. Unfortunately, later publications described that galanin(2-11) also binds with similar affinity to GalR3, a critical limitation when delineating the interplay between galanin receptor subtypes. Even so, galanin(2-11) has been given extensive attention and been used in numerous study as a non-GalR1 ligand. We here present several promising ligands that are GalR subtype selective and these might be future candidates to unravel the function of GalR subtypes. We are currently testing their signalling in order to find novel agonists/antagonists for each receptor, and prepare to test them in relevant biological systems.