Probing the steric space at the floor of the D_1 dopamine receptor orthosteric binding domain: 7α-, 7β-, 8α-, and 8β-methyl substituted dihydrexidine analogues

摘要

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 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-Me_(ax)-DHX (270 nM), 8α-Me_(eq)-DHX (920 nM), 7β-Me_(eq)-DHX (6540 nM), and 7α-Me_(ax)-DHX (>10000 nM). Molecular modeling studies suggest that although the disruption of an aromatic interaction between Phe203~(5.47) and Phe288 ~(6.51) is the cause for the 14-fold loss in affinity associated with 8β-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.