Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D₃ Receptor (D₃R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs)

Abstract

Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D 3 receptor (D 3 R) affinity (D 3 R K i = 12.0 nM) and selectivity (D 2 R/D 3 R ratio = 905). Herein, we present derivatives of 1 with comparable D 3 R affinity (32, D 3 R K i = 3.2 nM, D 2 R/D 3 R ratio = 60) and selectivity (30, D 3 R K i = 21.0 nM, D 2 R/D 3 R ratio = 934).Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D 3 R affinity (K i = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D 3 R K i = 23.9 nM), 1 was found to be more selective for the D 3 R among D 1 -and D 2 -like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazinecontaining D 3 R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D 3 R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D2 or D3 Receptor Agonists

“…To generate SAR, the new library of compounds was tested in radioligand binding assays at both human-cloned D 2 R (hD 2 R) and D 3 R (hD 3 R) receptor subtypes using agonist [ 3 H]-( R )-(+)-7-OH-DPAT and/or antagonist [ 3 H]- N -methylspiperone (Table ). We have found that the D 2 R active state agonist binding is significantly more sensitive ,,, to the radioligand used with respect to D 3 R. As a consequence, the use of [ 3 H]-( R )-(+)-7-OH-DPAT allows an accurate determination of apparent affinities for both targets, and selectivity, valuable to better correlate measured binding values with predicted and/or experimentally determined functional profiles, ,,, which would be otherwise dramatically overestimated in favor of the D 3 R when the antagonist [ 3 H]- N -methylspiperone is used [Table , comparison between D 3 R and D 2 R selectivity ratios between K i s obtained using [ 3 H]- N -methylspiperone or [ 3 H]-( R )-(+)-7-OH-DPAT].…”

Interaction of Ligands for PET with the Dopamine D3 Receptor: In Silico and In Vitro Methods

“…The molecular docking studies were performed using the previously reported methods [21]. Fallypride, FTP, and KX-02-065 structures were drawn using the ChemDraw Professional 15.1 (PerkinElmer Informatics, Inc., Waltham, MA, USA).…”

Identification of Novel Dopamine D2 Receptor Ligands—A Combined In Silico/In Vitro Approach

“…The dataset of inactives ( SC60 – SC127 ) was also derived from the ChEMBL and comprised 68 compounds with a K I higher than 50 µM. The inactive dataset is shown in Table S2 [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. The decoy dataset including 3752 compounds was generated utilizing the DUD-E webtool ( [ 93 ], accessed on 15 March 2021) and based on the structures of the active dataset.…”