Cognitive impairment is a core feature of many psychiatric and neurological disorders. Currently available therapies do not significantly improve cognitive impairment. Dopaminergic neurotransmission in the prefrontal cortex is important for the regulation of cognitive function and therapeutic interventions that modulate dopaminergic function in the cortex could improve cognition. The enzyme catechol-O-methyltransferase (COMT) is a key regulator of dopaminergic tone in the cortex and hippocampus and individual variability in COMT function is associated with differences in cognitive function. Tolcapone, a COMT inhibitor, has been approved as a treatment for the motor symptoms of Parkinson’s disease but it has multiple features that prevent its widespread use as a cognitive enhancer including poor pharmacokinetics (PK) that require 3X/day dosing in patients and a black box warning for potentially fatal liver toxicity. Carr’s team developed non-nitrocatechol, COMT inhibitors with improved PK and safety profiles compared to tolcapone. They will describe multiple novel compounds with promising preclinical in vivo profiles that may be suitable for clinical trials testing their cognitive enhancement capabilities.

The Summer Seminar Series is co-sponsored by INBT and the Physical Sciences-Oncology Center.