From Virtual to Real Screening for D3 Dopamine Receptor Ligands

Imbalance of the dopaminergic system is involved in various neurological and neuropsychiatric disorders, for example, Parkinson’s disease, schizophrenia, and drug abuse. Selective attraction of one dopamine receptor subtype could represent an improved therapeutic approach or at least a good way to evaluate the (patho)physiological functions of this subtype in the disorder. Here we focused on the dopamine D3 receptor, since this subtype plays an important neuroregulatory role in several diseases and possesses a distinct localization in the central nervous system. As D3 receptors display high sequence identity to D2 receptors, cross-reactivity is a problem for most compounds used. Although this field of research has been worked on for decades, many lead structures have unsatisfying selectivity. Since numerous described compounds with diverse structural elements showed some D3 receptor preference, we focused on these elements—first by virtual and then by real screening of the most promising compounds—to find new lead candidates for further optimization. Virtually screened synthetic compounds from collections of Specs (229 685 compounds from release June 2003, Specs, Delft, The Netherlands) and Interbioscreen (IBS; 25 601 compounds from release February 2004, Interbioscreen, Moscow, Russia) were investigated as potentially selective ligands at dopamine D3 receptors. We performed this screening by using analogues of BP897 (1), a D3 receptor-preferring partial agonist

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