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

PLOPER, DIEGO; PERNICONE, A.; TOMAS-GRAU, RODRIGO; MANZANO, V.; SOCÍAS, B.; TERÁN, MARÍA DEL MILAGRO; BUDEGUER, VALENTINA; SOSA-PADILLA, B.; GONZÁLEZ-LIZÁRRAGA, F.; ÁVILA, CÉSAR; GUAYAN, LAURA; CHAVES, S.; CRUZ, HERNÁN; VERA PINGITORE, E.; VARELA, O.; CHEHÍN, ROSANA

ACS Chemical Neuroscience

American Chemical Society

Lugar: Washington, DC; Año: 2024

The escalating prevalence of Parkinson´s disease (PD) underscores the need for innovativetherapeutic interventions since current palliative measures, including the standard L-Dopaformulations, face challenges of tolerance and side effects while failing to address theunderlying neurodegenerative processes. Here, we introduce DAD9, a novel conjugate moleculethat aims to combine symptomatic relief with disease-modifying strategies for PD. Craftedthrough knowledge-guided chemistry, the molecule combines a non-antibiotic doxycyclinederivative with dopamine, preserving neuroprotective attributes while maintainingdopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cellfunctions, and sustained antioxidant and anti-inflammatory properties of the tetracyclineprecursor. Furthermore, it effectively interfered with the formation and seeding of toxic -Synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 wasable to activate dopamine receptors, and docking simulations shed light onto the moleculardetails of this interaction. These findings position DAD9 as a potential neuroprotectivedopaminergic agonist, promising advancements in PD therapeutics.