Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D 3 Receptor (D 3 R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs)

J Med Chem. 2019 May 23;62(10):5132-5147. doi: 10.1021/acs.jmedchem.9b00412. Epub 2019 May 6.

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 D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity ( Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Conserved Sequence
  • Drug Design
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Radioligand Assay
  • Radiopharmaceuticals / pharmacokinetics
  • Receptors, Dopamine D3 / drug effects*
  • Receptors, G-Protein-Coupled / drug effects*
  • Receptors, Serotonin / drug effects
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Ligands
  • Radiopharmaceuticals
  • Receptors, Dopamine D3
  • Receptors, G-Protein-Coupled
  • Receptors, Serotonin
  • Spiro Compounds