Novel 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives as triple-target D2R/D3R/5-HT1AR agonists with robust antidepressant and antiparkinsonian activity

Abstract

Parkinson's disease (PD) patients cause substantial motor impairment in daily life, with approximately 40 % patients also exhibiting comorbid depression. Current therapy predominantly employs dopamine D₂R/D₃R agonists, whereas 5-HT_1AR activation confers clinically validated antidepressant benefits. Therefore, in this study, we report the discovery of compound 22b, a D₂R/D₃R/5-HT_1AR muti-target agonist, which demonstrates both enhanced antiparkinsonian and antidepressant-like activities. A new series of 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives were designed, synthesized, and evaluated for receptor activity and hERG inhibition. Among them, compound 22b showed potent agonistic activity at D₂R (EC₅₀ = 1.29 nM), D₃R (EC₅₀ = 1.05 nM) and 5-HT_1AR (EC₅₀ = 153.50 nM), with favorable metabolic stability (T_1/2p.o. = 3.77 h), neuroprotective effects and blood-brain barrier permeability (B/P = 0.348-0.506). In vivo, 22b significantly improved total distance traveled in MPTP-induced PD mouse models at 3 mg/kg (s.c.) and depressive-like behaviors in forced swim test in mice at low doses (1 mg/kg p.o.). These findings highlight 22b as a promising candidate for future exploration aiming at treatment of depression and Parkinson's disease.

Keywords: D(2)R/D(3)R/5-HT(1A)R muti-target agonist; Depression; Parkinson; Structural optimization.