Fishing for accessory binding sites at GPCRs with 'loop-hooks' - an approach towards selectivity? Part I

Receptor-subtype selectivity is an important issue in medicinal chemistry and can become very difficult to achieve if the actual binding pockets of the respective receptors are highly conserved. For such cases, known unselective ligands could be equipped with a spacer that sticks outside the actual orthosteric binding pocket towards the extracellular loops. The end of the spacer bears certain functional groups to enable specific or unspecific interactions with the receptor residues outside the binding cavity. Our experiments indicated that it is possible to achieve selectivity within the dopamine D1 family with such 'loop-hooks'.