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

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