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

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


Author Cueva J.P.
Gallardo-Godoy A.
Juncosa J.I.
Vidi P.A.
Lill M.A.
Watts V.J.
Nichols D.E.
Title 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
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2011-08-01
Sub-type Article (original research)
DOI 10.1021/jm200334c
Volume 54
Issue 15
Start page 5508
End page 5521
Total pages 14
Place of publication Washington DC United States
Publisher American Chemical Society
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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