High‐throughput screening for identification of novel allosteric modulators of the D 3 dopamine receptor

Abstract

Dopamine receptors (DARs) are involved in the treatment of many neuropsychiatric disorders including schizophrenia and Parkinson's disease. Many currently available dopaminergic drugs modulate multiple receptor subtypes due to high homology in their orthosteric binding sites, leading to potential side effects. As an approach to discover highly selective allosteric modulators for the D3 DAR, our lab employed high throughput screening technologies. The NIH Molecular Libraries Program 400,000+ small molecule library was initially screened using a D3 DAR-mediated β-arrestin recruitment assay. Confirmation and counter-screens were performed to obtain an initial assessment of selectivity and mechanisms of action and identified 57 potential negative allosteric modulators (NAMs), 63 potential positive allosteric modulators (PAMs), and 62 potential allosteric agonists. Further triage and characterization identified several D3 DAR-selective putative NAMs, PAMs, and allosteric agonists that are currently being characterized using additional assays to confirm their selectivity, activity, and mechanism of action. As D3-preferring D2/D3 DAR orthosteric agonists show promise as neuroprotective/neurorestorative agents, we conducted preliminary studies using one of the lead allosteric agonists, and found that it displays neuroprotective properties using a cell culture model system. We ultimately hope that these probes will prove useful as in vitro and in vivo pharmacological tools or leads for therapeutic drugs.