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.
Cueva, J. P., Gallardo-Godoy, A., Juncosa, J. I., Vidi, P. A., Lill, M. A., Watts, V. J., & Nichols, D. E. (2011). 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. Journal of Medicinal Chemistry, 54(15), 5508-5521. https://doi.org/10.1021/jm200334c