The development of selective dopamine receptor agonists is a subject of increasing interest due to the potential therapeutic applications in neurological disorders. Due to the large degree of homogeneity among the D2-like family of dopamine receptors, achieving ligands capable of discrimination among them remains a significant challenge. Previous work from our lab has shown the use of bitopic ligands to be a powerful strategy in achieving increased D3R selectivity for antagonists. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128907 and PF592379, we sought to synthesize and test a variety of bitopic structures to further improve their D3R selectivity. When in a bitopic configuration, the (S,S) conformation of the PF592379 primary pharmacophore resulted in a privileged architecture with increased affinity and selectivity for the D3R orthosteric binding site. Driven by an earlier finding revealing the inclusion of a cyclopropyl moiety in the linker of the bitopic molecule may induce a structural orientation favorable for D3R selectivity and allosteric modulations, we proceeded to synthesize the bitopic compounds of the privileged (S,S)-PF592379 primary pharmacophore with a cyclopropyl ring in the linker. Incorporation of the ring in the linker and full resolution of the chiral centers present allowed us to analyze the effect of the stereochemistry of the linker on the final affinity and selectivity of the bitopic molecules synthesized. Binding studies were performed in presence of agonist radioligand, to specifically assess affinities for the receptors’ active states. Lead compound FOB02-04 (D2R Ki: 106 nM, D3R Ki: 2.84 nM, D4R Ki: 315 nM, D2R/D3R: 37.3, D4R/D3R: 111) and its most active enantiomer FOB02-04A (D2R Ki: 87.8 nM, D3R Ki: 1.85 nM, D4R Ki: 286 nM, D2R/D3R: 47.5, D4R/D3R: 155), may have the highest D3R to D2R selectivity reported for agonists, to date. The high structural complexity of these compounds may inspire future computational studies to better understand ligand-receptor interactions, as well as underscore potential biased agonism as a consequence of specific receptor conformations. Moreover, due to their high D3R selectivity and metabolic stability in mice liver microsomes, FOB02-04 and the eutomer FOB02-04A, may have the potential to become the main pharmacological reference tools for future D3R in vitro and/or in vivo studies.

Significance of chirality in drug design and synthesis of bitopic ligands as D3R selective agonists

2019 Fall National Meeting

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