Abstract Study Objectives We recently proposed dopamine D3 receptor (D3R) antagonists as a potential therapy for restless legs syndrome (RLS). To test this hypothesis, we evaluated two selective D3R ligands, PG01042 and PG01037, in a brain iron-deficient rat model of RLS. Their biochemical properties were also characterized and compared with pramipexole, a commonly used D2-like receptor agonist for RLS. Methods Periodic leg movements (PLM) during sleep and wake and sleep fragmentation were analyzed in rats with an iron deficient diet during the postweaning period. Go protein activation and β-arrestin1 and β-arrestin2 recruitment were analyzed with BRET methodology in HEK-293T cells expressing D3Rs and in cells co-transfected with D3R and D1R. Molecular dynamic simulations were additionally performed to define the distinct molecular profiles of PG01042 and PG01037. Results In iron-deficient rats, PG01042 and PG01037 produced opposite behavioral effects, with PG01042 dose-dependently reducing motor symptoms and improving sleep quality, whereas PG01037 dose-dependently exacerbated motor symptoms without improving sleep. Compared with pramipexole, PG01042 behaved as a D3R partial agonist at both G protein activation and β-arrestin recruitment. In contrast, PG01037 behaved as a partial agonist for β-arrestin recruitment while exhibiting inverse agonism at G protein activation. Co-transfection with the D1R abrogated the partial efficacy of both compounds at β-arrestin recruitment. The differences in G protein activation between both ligands were attributed to subtle variations in the positioning of the chloro substituents on their 2,3-dichlorophenyl moiety. Conclusions These findings highlight the therapeutic potential of D3R ligands with the distinct pharmacological profile of PG01042 in RLS.
Lai et al. (Thu,) studied this question.