Design and Synthesis of DR 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 DR-selective compound. The effect of the flexible linker (,-), SBFs (,-), and the chirality of orthosteric binding fragments (OBFs) (,, , ,, ,, and ,) 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 of the DR, thereby reducing the DR affinity to a suboptimal level.

Synthesis of bitopic ligands based on fallypride and evaluation of their affinity and selectivity towards dopamine D and D receptors.

The difference in the secondary binding site (SBS) between the dopamine 2 receptor (DR) and dopamine 3 receptor (DR) has been used in the design of compounds displaying selectivity for the DR versus DR. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for DR versus DR. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in DR versus DR selectivity.