New Dopamine D3-Selective Receptor Ligands Containing a 6-Methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol Motif

Abstract

A series of analogues featuring a 6-methoxy-1,2,3,4-tetrahydroisoquinolin-7ol unit as the arylamine "head" group of a classical D3 antagonist core structure were synthesized and evaluated for affinity at dopamine D1, D2, and D3 receptors (D1R, D2R, D3R). The compounds generally displayed strong affinity for D3R with very good D3R selectivity. Docking studies at D2R and D3R crystal structures revealed that the molecules are oriented such that their arylamine units are positioned in the orthosteric binding pocket of D3R, with the arylamide "tail" units residing in the secondary binding pocket. Hydrogen bonding between Ser 182 and Tyr 365 at D3R stabilize extracellular loop 2 (ECL2), which in turn contributes to ligand binding by interacting with the "tail" units of the ligands in the secondary binding pocket. Similar interactions between ECL2 and the "tail" units were absent at D2R due to different positioning of the D2R loop region. The presence of multiple H-bonds with the phenol moiety of the headgroup of 7 and Ser192 accounts for its stronger D3R affinity as compared to the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinecontaining analogue 8.

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Some representatives of diazaspiro alkane [ 142 ] and 6-methoxy-1,2,3,4-tetrahydroquinolin-7-ol derivatives [ 143 ] showed high affinity (Ki < 20 nM) and high selectivity (D2R/D3R ratio: 200–1000) antagonists for D3R under in vitro conditions but the pharmacokinetic properties or their in vivo actions were not reported.…”

Inclusion of enclosed hydration effects in the binding free energy estimation of dopamine D3 receptor complexes

“…The mechanism of antagonism of D3 receptors has been intensely studied to gain an understanding of how to develop potent and selective antagonists. [22, 28, 30, 36, 37] The crystal structure of the D3 receptor in complex with eticlopride, [28] a dual D2/D3 antagonist, has been very helpful in understanding the intermolecular interactions in the orthosteric binding site (OBS) of the D3 receptor. It also revealed a secondary binding site (SBS) which is believed to be a critical molecular recognition site.…”

“…[36] These important discoveries have provided valuable information for the development of D3 selective ligands. [22, 23]…”

Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands

“…This interaction was previously characterized as fundamental for binding to the OBS of D 2 R. In addition, two recently reported docking studies on D 2 R cocrystal structure further support our results regarding predicted binding modes of ligands. [57,58] In series of p-monosubstituted SF 5 derivatives (7i and 7j), m-monosubstituted SF 5 derivatives (7g and 7h), and p,m-disubstituted derivative with the same linker length (7c), docking results indicate that F I G U R E 2 Docking results of 7i into the binding site of (a) D 3 R and (b) D 2 R. The left side of the figure corresponds to the three-dimensional (3D) representation of binding sites, whereas the right side of the figure corresponds to the comparative 2D interaction plots obtained for 7i and cocrystal ligands (a, eticlopride; b, risperidone). Encircled residues on 2D interaction plots represent residues that are engaged in interactions with both ligands m-substitution is responsible for achieving an optimal interaction with Tyr 408 7.34 (Figure S5).…”