Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D2/D3 Receptor Bitopic Ligands

J Med Chem. 2021 Oct 28;64(20):15313-15333. doi: 10.1021/acs.jmedchem.1c01353. Epub 2021 Oct 12.

Abstract

The crystal structure of the dopamine D3 receptor (D3R) in complex with eticlopride inspired the design of bitopic ligands that explored (1) N-alkylation of the eticlopride's pyrrolidine ring, (2) shifting of the position of the pyrrolidine nitrogen, (3) expansion of the pyrrolidine ring system, and (4) incorporation of O-alkylations at the 4-position. Structure activity relationships (SAR) revealed that moving the N- or expanding the pyrrolidine ring was detrimental to D2R/D3R binding affinities. Small pyrrolidine N-alkyl groups were poorly tolerated, but the addition of a linker and secondary pharmacophore (SP) improved affinities. Moreover, O-alkylated analogues showed higher binding affinities compared to analogously N-alkylated compounds, e.g., O-alkylated 33 (D3R, 0.436 nM and D2R, 1.77 nM) vs the N-alkylated 11 (D3R, 6.97 nM and D2R, 25.3 nM). All lead molecules were functional D2R/D3R antagonists. Molecular models confirmed that 4-position modifications would be well-tolerated for future D2R/D3R bioconjugate tools that require long linkers and or sterically bulky groups.

Publication types

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / metabolism*
  • Salicylamides / chemical synthesis
  • Salicylamides / chemistry
  • Salicylamides / pharmacology*
  • Structure-Activity Relationship

Substances

  • Ligands
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Salicylamides
  • eticlopride