Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D 2 /D 3 Receptor Bitopic Ligands.

The crystal structure of the dopamine D ₃ receptor (D ₃ R) 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 D ₂ R/D ₃ R 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 (D ₃ R, 0.436 nM and D ₂ R, 1.77 nM) vs the N -alkylated 11 (D ₃ R, 6.97 nM and D ₂ R, 25.3 nM). All lead molecules were functional D ₂ R/D ₃ R antagonists. Molecular models confirmed that 4-position modifications would be well-tolerated for future D ₂ R/D ₃ R bioconjugate tools that require long linkers and or sterically bulky groups.