The binding affinity and recognition specificity of dopamine to human dopamine receptors can be rationally altered by halogen doping.

Human hepta-helical transmembrane spanning G protein-coupled family of dopamine receptors (DRs) play key neurophysiological roles and are involved in the pathogenesis of Parkinson's disease due to dopamine deficiency. Previous studies found that halogen doping can be used as a chemical strategy to control the optical and spectroscopic properties of dopamine molecule and to shift the binding mode of various exogenous compounds to DRs. In this study, we attempted to investigate the halogen-doping effects by substituting the three positions (X1, X2 and X3) of dopamine's aromatic phenyl group with four halogen atoms (F, Cl, Br and I) on the binding affinity and recognition specificity of halogen-doped dopamine analog ligands to five DR receptors. A systematic halogen-doping substitution profile was created computationally, from which a number of very favorable substitutions (VFSs) and very unfavorable substitutions (VUSs) were identified, and their conformational and energetic properties were examined in the modeled complex structures with DRs, revealing that some VFSs can be attributed to the formation of additional halogen bond (X-bond) or hydrogen bond (H-bond) between DR receptors and halogen-doped analog ligands upon the substitutions. Fluorescence analysis observed that the dopamine binds potently to D1 and D2, with a moderate selectivity (⌂KDD2/D1 = 0.5-fold) for D2 over D1, which can be improved considerably to D1 upon the iodine substitution at X2 position (X2-I) or upon the bromine substitution at X3 position (X3-Br), but the two substitutions have only a moderate effect on dopamine affinity to D2. Consequently, the dopamine selectivity between D1 and D2 was reversed by the two substitutions, that is, the selectivity was changed from D2-over-D1 (native dopamine, ⌂KDD2/D1 = 0.5-fold) to D1-over-D2 (⌂KDD2/D1 = 18.9-fold upon X2-I substitution and 1.8-fold upon X3-Br substitution). This work demonstrated that the binding affinity and recognition specificity of dopamine ligand to different DR receptors can be rationally altered by careful design of halogen types and their substitution positions on dopamine's aromatic ring.