PROJECT SUMMARY Major depressive disorder (MDD) is a serious, debilitating, and often recurring disorder with a substantial lifetime risk and a high societal cost. Depressed patients frequently display a variety of co-morbid symptoms, including depressed moods, loss of motivation and/or reductions in the ability to experience pleasure (anhedonia), loss of interest and energy, combined with psychological and vegetative changes such as sleep and/or appetite disturbances, fatigue, feelings of guilt and despair, difficulties in maintaining mental focus, and recurrent thoughts of suicide. MDD often occurs together with other common illnesses, including both physical and psychiatric disorders. Currently available antidepressant drugs display limited efficacy, slow onset of action, and are hampered by unwanted side effects. Traditional antidepressant drugs act through serotonergic and noradrenergic systems. Although newer drugs acting through glutamatergic systems show some promise, there remains considerable unmet need for improved medications. Central dopaminergic systems have been identified as an alternative target, particularly through the involvement of dopamine in reward, anhedonia, and related functions. Indeed, several clinical studies demonstrate benefit with direct and indirect dopamine agonists in MDD. As a key enzyme in dopamine metabolism, catechol-O-methyl transferase (COMT) has emerged as an attractive target for the treatment of various central and peripheral nervous systems disorders, including MDD, Parkinson’s disease, and other dopamine-related disorders. Two forms of COMT exist, a soluble form (S-COMT) in peripheral tissues, and a membrane-bound form (MB-COMT), mainly expressed in the brain. Current COMT inhibitors in the clinic contain a nitrocatechol moiety that is associated with poor brain penetration and toxicity. To overcome these problems, Psy Therapeutics is developing a series of brain-penetrant small molecule inhibitors of COMT based on novel scaffolds lacking a nitrocatechol group that were discovered using a DNA encoded library screen. Preliminary structure activity relationship (SAR) efforts led to the identification of COMT inhibitors with good microsomal stability, good brain penetration, and potent inhibition of S-COMT and MB_COMT. The goal of this Phase I application is to pursue further lead optimization efforts to enhance the potency against both S- and MB-COMT and in vitro pharmacological profile (aim 1). In aim 2 we will evaluate pharmacokinetics and biomarkers of dopamine metabolism to identify COMT inhibitors with improved oral bioavailability and brain penetration that inhibit COMT in vivo. The ability of these compounds to modulate reward responsivity and learning will be assessed in aim 3 using a touchscreen Probabilistic Reward Task (PRT) model in mice, with tolcapone as control, as a preclinical model with outcomes very similar to human studies. Successful completion of this proposal will identify a novel COMT inhibitor as a candidate drug to advance to IND enabling studies as a potential new treatment for depression.

PROJECT NARRATIVE Many antidepressant drugs fail in the clinic because preclinical models do not translate well into humans. In this proposal Psy will address a desperate need to develop novel safe and effective antidepressants by developing potent, selective, and brain penetrant COMT inhibitors as a potential therapy for the treatment of depression and other disorders of the dopamine system. This project will evaluate the ability of brain penetrant COMT inhibitors to modulate reward responsivity and learning using a touchscreen Probabilistic Reward Task model in mice, as a translational model with outcomes very similar to human studies.