Towards synthetic adrenaline receptors

Inspired by the complex and highly efficient molecular recognition of adrenaline by its biological receptor, small synthetic models were prepared which mimick parts of the natural binding mode. The basic module demonstrates that strong electrostatic as well as hydrogen bond attractions by benzylic bisphosphonates are indeed a powerful general tool for the recognition of amino alcohols. In the following generation, a hydrophobic binding pocket was introduced, which leads to much stronger binding in more polar solvents. Its cavity, however, is too large to distinguish between adrenaline derivatives and amino acids so that a third generation was designed, into which the adrenaline molecule fitted snugly. This time, amino acids were rejected and only guests with the slim dopamine-skeleton were bound efficiently. With this host, a shape-selective adrenaline recognition could be achieved for the first time in water. However, even this host is surprisingly flexible. In order to replace the huge mass of seven membrane-spanning helices in the natural receptor with a low molecular weight macrocycle, elements of much higher rigidity were implemented into the fourth generation of new adrenaline hosts, which should have a high degree of functional group preorganization and therefore lead to enhanced binding strength in the physiological solvent—water.