Distinct pharmacological profile of a dopamine D3 receptor ligand with potential therapeutic effect in restless legs syndrome
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ID: 313468
2026
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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.
| Reference Key |
openalex_W7161308850
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| Authors | Yuan‐Yang Lai, Bradley M. Keegan, Marc Ciruela-Jardí, Jian Jing Cao, Kung‐Chiao Hsieh, Christopher J Earley, Lei Shi, Estefanía Moreno, Leonardo Pardo, A H Newman, Jerome M Siegel, Sergi Ferré |
| Journal | Sleep & breathing = Schlaf & Atmung |
| Year | 2026 |
| DOI |
10.1093/sleep/zsag134
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| URL | |
| Keywords | Keywords not found |
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