Design and Synthesis of D 3 R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies.

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D ₃ R-selective compound. The effect of the flexible linker ( ( R , S ) -trans -2a - d ), SBFs ( ( R , S ) -trans -2h - j ), and the chirality of orthosteric binding fragments (OBFs) ( ( S , R ) -trans -d , ( S , R ) -trans -i , ( S , S ) -trans -d , ( S , S ) -trans -i, ( R , R ) -trans -d, and ( R , R ) -trans -i ) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP110 ^3.32 of the D ₃ R, thereby reducing the D ₃ R affinity to a suboptimal level.