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.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Cueva
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gallardo-Godoy
authors.forename: Jose I
authors.initials: JI
authors.lastname: Juncosa
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Vidi
authors.forename: Markus A
authors.initials: MA
authors.lastname: Lill
authors.forename: Val J
authors.initials: VJ
authors.lastname: Watts
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010617:Phenanthridines / Q000138:chemical synthesis / Q000378:metabolism*; D011485:Protein Binding; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018491:Dopamine Agonists; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C061532:dihydrexidine