Synthesis of bitopic ligands based on fallypride and evaluation of their affinity and selectivity towards dopamine D2 and D3 receptors

Abstract

The difference in the secondary binding site (SBS) between the dopamine 2 receptor (D₂R) and dopamine 3 receptor (D₃R) has been used in the design of compounds displaying selectivity for the D₃R versus D₂R. 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 D₃R versus D₂R. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in D₃R versus D₂R selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing D₃R affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for D₃R versus D₂R and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the D₃R. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for D₃R versus D₂R.

Keywords: Bitopic ligands; Dopamine 2 receptor; Dopamine 3 receptor; Fallypride; PET imaging.