Neurodegenerative diseases, such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases, are characterized by the loss of neurons' structure and function or by neuronal death in the advanced pathological stage. One of the underlying reasons is an imbalance of dopamine in the CNS, a neurotransmitter responsible for mood, movement, behavior, cognition, memory, and attention. Further, it was proposed that restoration of dopamine levels may inhibit neuroinflammation of the brain tissue. Thus, restoration of dopamine levels in the CNS can provide an advantage in treating certain neurodegenerative disorders.<br/><br/>Recently, our lab has reported a novel class of urea analogs capable of inhibiting Dopamine Active Transporter (DAT) with a high degree of selectivity and potency. To evaluate DAT inhibitors' effect on CNS-induced inflammation, we have tested our lead compound with the optimal pharmacokinetic profile in the experimental autoimmune encephalomyelitis (EAE) mouse model mimicking clinical signs of multiple sclerosis. We observed that this compound has statistically significant anti-inflammatory effects and attenuates motor deficits and pain behaviors. Here we present the project's current status, providing more insights into the structural features of the molecule responsible for the observed activity.

Urea-based dopamine transporter inhibitors for the treatment of neurodegenerative diseases

ACS Fall 2021

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