Title |
Probing the Steric Space at the Floor of the D1 Dopamine Receptor Orthosteric Binding Domain: 7α-, 7β-, 8α-, and 8β-Methyl Substituted Dihydrexidine Analogues
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Published in |
Journal of Medicinal Chemistry, July 2011
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DOI | 10.1021/jm200334c |
Pubmed ID | |
Authors |
Juan Pablo Cueva, Alejandra Gallardo-Godoy, Jose I. Juncosa, Pierre A. Vidi, Markus A. Lill, Val J. Watts, David E. Nichols |
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 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. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 15 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 4 | 27% |
Professor > Associate Professor | 3 | 20% |
Student > Master | 2 | 13% |
Researcher | 2 | 13% |
Professor | 1 | 7% |
Other | 2 | 13% |
Unknown | 1 | 7% |
Readers by discipline | Count | As % |
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Pharmacology, Toxicology and Pharmaceutical Science | 1 | 7% |
Neuroscience | 1 | 7% |
Agricultural and Biological Sciences | 1 | 7% |
Other | 0 | 0% |
Unknown | 3 | 20% |