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.
- New molecular tools for the discovery of, and research into, D3R physiology
- Therapeutic use for neurodegenerative disorders such as Parkinson’s Disease and Restless Legs Syndrome
- Neurological and neuropsychiatric disorders associated with dopamine dysregulation
- The agonists have unique high D3R affinity and selectivity over D2R
- Potentially fewer side effects due to high selectivity toward D3R
- Broad range of clinical applications for the treatment neurological and neuropsychiatric disorders associated with dopamine dysregulation
Battiti FO, et al. The significance of chirality in drug design and synthesis of bitopic ligands as d3 receptor (d3r) selective agonists [PMID: 31257877]
- U.S. Provisional: U.S. Provisional Patent Application Number 62/833,023 , Filed 12 Apr 2019
- PCT: PCT Application Number PCT/US2020/027903 , Filed 13 Apr 2020