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

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.