Probing the steric space at the floor of the D1 dopamine receptor orthosteric binding domain: 7?-, 7?-, 8?-, and 8?-methyl substituted dihydrexidine analogues.

ABSTRACT: 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?-axial, 8?-equatorial, and 7?-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7?-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?-Me(ax)-DHX (270 nM), 8?-Me(eq)-DHX (920 nM), 7?-Me(eq)-DHX (6540 nM), and 7?-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 8?-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.

SUBMITTER: Cueva JP 

PROVIDER: S-EPMC3150624 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature