Due to the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. The development of subtype-selective pharmaceutical small molecules to activate (agonists) signals regulated by D2-like receptors has been especially difficult.
The inventors at the National Institute on Aging (NIDA) have recently synthesized a new generation of D3R selective agonists by applying a well-established bitopic molecular approach. Inventors were able to combine a primary pharmacophore (PP) with a secondary pharmacophore (SP) to generate compounds with high D3R subtype affinity and selectivity (e.g., compound 53). All newly synthesized compounds were tested in radioligand competition binding studies for D2-like receptor affinities (D2R, D3R, and D4R). Compound 53 and its eutomer, 53a were further evaluated for metabolic stability in rat liver microsomes and metabolite identification to confirm their applicability to future in vivo studies.
The molecules could not only serve as a tools for studying D3R dopaminergic signaling but have the potential to become a pharmacological treatment of neurodegenerative disorders associated with dopaminergic dysregulation. The characterization of these D3R specific agonists including compound 53 and 53a is further described in the listed manuscript (PMID: 31257877) and claimed in the referenced patent application below. The inventors have future plans to develop these compounds as molecular tools which will be appealing to a large group of scientists working in molecular biology, pharmacology, and computational sciences directed toward dopamine D3R and their multi-therapeutic potential. The syntheses and in vitro characterization are completed. Potential application as therapeutics is also a collaboration interest of the inventors.