Matsupexole: A novel nonergot dopamine receptor agonist with sustained efficacy in a rat model of Parkinson's disease and limited off-target activity.

Abstract

BACKGROUND AND PURPOSE: Dopamine receptor agonists, particularly targeting the dopamine Dreceptor (DR), have been used to treat Parkinson's disease (PD). However, valvular heart disease and somnolence, mainly caused by activating the serotonin 5-HTreceptor (5-HTR) and dopamine Dreceptor (DR), 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 DR and a 6-hydroxydopamine-lesioned male rat PD model. To explore its adverse effects, the agonist activity for other receptors, including 5-HTR and DR, 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 DRs without inducing 5-HTR activation or promoting PHVIC proliferation. Matsupexole demonstrated sustained efficacy in the PD model. In contrast, despite its strong DR agonist activity, cabergoline, an ergot dopamine receptor agonist, significantly evoked PHVIC proliferation. Reflecting its higher DR/DR selectivity, matsupexole did not affect non-REM sleep induction. Although pramipexole, a DR-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 Val190in DR and matsupexole, but not pramipexole, further supports the higher DR/DR selectivity of matsupexole. CONCLUSION AND IMPLICATIONS: Matsupexole is a promising future, potentially best-in-class dopamine receptor agonist for treating PD.