DESIGN, SYNTHESIS, AND EVALUATION OF A NOVEL CONJUGATE MOLECULE WITH DOPAMINERGIC AND NEUROPROTECTIVE ACTIVITIES FOR PARKINSON’S DISEASE

PLOPER, DIEGO ; PERNICONE, AGUSTÍN ; RODRIGO H. TOMAS-GRAU ; VERÓNICA MANZANO; SERGIO B. SOCÍAS ; MARÍA DEL MILAGRO TERÁN; VALENTINA BUDEGUER ISA; BERNARDO SOSA-PADILLA ; FLORENCIA GONZÁLEZ-LIZÁRRAGA; CÉSAR L. AVILA ; MARÍA LAURA GUAYÁN; SILVINA CHAVES ; HERNÁN CRUZ; ESTEBAN VERA PINGITORE; OSCAR VARELA; ROSANA CHEHÍN

ACS Chemical Neuroscience

American Chemical Society, ACS Publications

Lugar: Washington DC; Año: 2024

1948-7193

The escalating prevalence of Parkinson´s disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard L-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9, a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a non-antibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions, and sustained antioxidant and anti-inflammatory properties of the tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic -Synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed light onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.