Dopamine receptor ligands have been studied for CNS disorders such as Parkinson’s disease (PD) and schizophrenia. Recent studies have shown a therapeutic role for dopamine 4 receptor antagonists in treating PD L-DOPA-induced dyskinesias (PD-LIDs). A compound with antagonistic activity at the D4 receptor was previously shown to have efficacy in lessening LIDs in 6-OHDA rodents and MPTP-lesioned nonhuman primate (NHP) models (by more than 59% in NHPs); however, this compound had significant locomotor effects, which lessens the therapeutic potential. In previous studies, our lab has shown a morpholine-based D4 antagonist is active in an in vivo rodent model of PD-LIDs without locomotor issues. We have identified multiple new scaffolds that provide excellent starting points for a medicinal chemistry optimization campaign. Through this campaign, we also discovered compounds with a high affinity and selectivity for the sigma-1 receptor. Studies have implicated sigma-1 receptors in schizophrenia, depression, dementia, addiction, and pain. There was one small-molecule antagonist in clinical trials, but further development has been halted, possibly due to poor oral bioavailability. Herein we report our SAR efforts to develop potent and selective D4 antagonists and sigma-1 modulators. We will use the availability of the crystal structures of both receptors to enable structure-based drug design.

Development of D4 antagonists and sigma-1 receptor modulators for the treatment of CNS disorders

ACS Spring 2022

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