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

Journal of Medicinal Chemistry
2011.0

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.

Knowledge Graph

Similar Paper

Probing the Steric Space at the Floor of the D<sub>1</sub> Dopamine Receptor Orthosteric Binding Domain: 7α-, 7β-, 8α-, and 8β-Methyl Substituted Dihydrexidine Analogues
Journal of Medicinal Chemistry 2011.0
Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines
European Journal of Medicinal Chemistry 2012.0
Further Definition of the D<sub>1</sub> Dopamine Receptor Pharmacophore:  Synthesis of trans-6,6a,7,8,9,13b-Hexahydro-5H-benzo[d]naphth[2,1-b]azepines as Rigid Analogues of β-Phenyldopamine
Journal of Medicinal Chemistry 1997.0
Evaluation of cis- and trans-9- and 11-Hydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridines as Structurally Rigid, Selective D1 Dopamine Receptor Ligands
Journal of Medicinal Chemistry 1995.0
Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor ligands with extended functionality for probing the secondary binding pocket
Bioorganic &amp; Medicinal Chemistry Letters 2018.0
Synthesis and pharmacological characterization of 2-(4-chloro-3-hydroxyphenyl)ethylamine and N,N-dialkyl derivatives as dopamine receptor ligands
Journal of Medicinal Chemistry 1992.0
Synthesis and dopamine receptor affinities of 2-(4-fluoro-3-hydroxyphenyl)ethylamine and N-substituted derivatives
Journal of Medicinal Chemistry 1990.0
Assessment of dopamine D1 receptor affinity and efficacy of three tetracyclic conformationally-restricted analogs of SKF38393
Bioorganic &amp; Medicinal Chemistry 2011.0
Synthesis and dopaminergic binding of 2-aryldopamine analogs: phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes
Journal of Medicinal Chemistry 1986.0
The replacement of the 2-methoxy substituent of N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine improves the selectivity for 5-HT1A receptor over α1-adrenoceptor and D2-like receptor subtypes
European Journal of Medicinal Chemistry 2017.0