This technology relates to the description and therapeutic use of a small molecule that selectively binds to and activates the D3 dopamine receptor. Dopamine receptors (DARs) are members of the G protein-coupled receptor (GPCR) superfamily that play a critical role in cell signaling processes, especially modulating the transfer of information within the nervous system. Members of the DAR subfamilies share high sequence homology, especially the D2 and D3 DARs. Most currently available dopaminergic drugs cross-react with both subtypes to varying degrees. Research indicates that D3 agonism may have important therapeutic potential while D2 agonism may induce negative side effects. Despite numerous attempts to produce D3 selective modulators, current FDA-approved drugs display relatively poor selectivity between the closely related D2 and D3 DARs. Our best representative analog shows a more selective profile to D3 DAR compared to the best previously reported selective D3 DAR agonist in the literature.
Selective D3 DAR agonists could offer improved therapy of disorders currently treated with relatively nonselective D3/D2 DAR agonists, including Parkinson’s Disease and Restless Leg Syndrome. The most significant impact on the patient population is likely to be in the treatment of Parkinson’s Disease, which has an estimated national economic burden of $14.4 billion, with costs projected to increase substantially over the coming decades as the American population ages.
Current FDA-approved treatments for Parkinson’s Disease are relatively nonselective agonists of the D3/2 DAR subtypes. Through a high-throughput screening campaign and systematic medicinal chemistry efforts, we have identified and developed a series of novel, highly selective small molecule D3 DAR agonists which can be further developed as agents for potential treatment of dopaminergic diseases. The best representative analog in this chemical scaffold shows a more selective profile compared to the best previously reported selective D3 DAR agonist in the literature.