Work

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

Year: 2019

Type: article

Abstract: Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4 H -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 piperazine-containing 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.9b00412