Probing the Steric Space at the Floor of the D1 Dopamine Receptor Orthosteric Binding Domain: 7α-, 7β-, 8α-, and 8β-Methyl Substituted Dihydrexidine Analogues

To probe the space at the floor of the orthosteric ligand binding site in the dopamine D1 receptor, four methylated analogues of dihydrexidine (DHX) were synthesized with substitutions at the 7 and 8 positions. The 8α-axial, 8β-equatorial, and 7α-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7β-axial analogue was prepared by an intramolecular Henry reaction. All of the methylated analogues displayed losses in affinity when compared to DHX (20 nM): 8β-Meax-DHX (270 nM), 8α-Meeq-DHX (920 nM), 7β-Meeq-DHX (6540 nM), and 7α-Meax-DHX (>10000 nM). Molecular modeling studies suggest that although the disruption of an aromatic interaction between Phe2035.47 and Phe2886.51 is the cause for the 14-fold loss in affinity associated with 8β-axial substitution, unfavorable steric interactions with Ser1073.36 result in the more dramatic decreases in binding affinity suffered by the rest of the analogues.