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

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• 作者：Juan Pablo Cueva ; Alejandra Gallardo-Godoy ; Jose I. Juncosa ; Jr. ; Pierre A. Vidi ; Markus A. Lill ; Val J. Watts ; David E. Nichols
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5508-5521
• 全文大小：1192K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

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 8伪-axial, 8尾-equatorial, and 7伪-equatorial were synthesized by photochemical cyclization of appropriately substituted N-benzoyl enamines, and the 7尾-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尾-Me_ax-DHX (270 nM), 8伪-Me_eq-DHX (920 nM), 7尾-Me_eq-DHX (6540 nM), and 7伪-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尾-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.