Background and purpose: Dopamine receptor agonists, particularly targeting the dopamine D_2L receptor (D_2LR), have been used to treat Parkinson's disease (PD). However, valvular heart disease and somnolence, mainly caused by activating the serotonin 5-HT_2B receptor (5-HT_2BR) and dopamine D₃ receptor (D₃R), respectively, currently challenge their clinical use. Here, we aimed to develop a novel dopamine receptor agonist with superior therapeutic efficacy for PD, while minimising adverse reactions.

Experimental approach: Matsupexole, a novel nonergot dopamine receptor agonist, was evaluated by agonist activity for D_2LR and a 6-hydroxydopamine-lesioned male rat PD model. To explore its adverse effects, the agonist activity for other receptors, including 5-HT_2BR and D₃R, and the resulting porcine heart valve interstitial cell (PHVIC) proliferation and non-rapid eye movement (REM) sleep induction in male rats were evaluated, in comparison with existing dopamine receptor agonists.

Key results: Matsupexole exhibited potent agonist activity for D_2LRs without inducing 5-HT_2BR activation or promoting PHVIC proliferation. Matsupexole demonstrated sustained efficacy in the PD model. In contrast, despite its strong D_2LR agonist activity, cabergoline, an ergot dopamine receptor agonist, significantly evoked PHVIC proliferation. Reflecting its higher D_2LR/D₃R selectivity, matsupexole did not affect non-REM sleep induction. Although pramipexole, a D₃R-favouring nonergot agonist, showed efficacy in the rat PD model, its effect was shorter in duration, and it strongly promoted non-REM sleep. The stabilised interaction between Val190^5.39 in D_2LR and matsupexole, but not pramipexole, further supports the higher D_2LR/D₃R selectivity of matsupexole.

Conclusion and implications: Matsupexole is a promising future, potentially best-in-class dopamine receptor agonist for treating PD.