Probing the Steric Space at the Floor of the D(1) Dopamine Receptor Orthosteric Binding Domain: 7 alpha-, 7 beta-, 8 alpha-, and 8 beta-Methyl Substituted Dihydrexidine Analogues

To probe the space at the floor of the orthosteric ligand binding site in the dopamine D(1) receptor, four methylated analogues of dihydrexidine (DHX) were synthesized with substitutions at the 7 and 8 positions. The 8 alpha-axial, 8 beta-equatorial, and 7 alpha-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7 beta-axial analogue was prepared by an intramolecular Henry reaction. All of the methylated analogues displayed losses in affinity when compared to DHX (20 nM): 8 beta-Me(ax)-DHX (270 nM), 8 alpha-Me(eq)-DHX (920 nM), 7 beta-Me(eq)-DHX (6540 nM), and 7 alpha-Me(ax)-DFLX (>10000 nM). Molecular modeling studies suggest that although the disruption of an aromatic interaction between Phe203(54.7) and Phe288(6.51) is the cause for the 14-fold loss in affinity associated with 8 beta-axial substitution, unfavorable steric interactions with Ser107(3.36) result in the more dramatic decreases in binding affinity suffered by the rest of the analogues.