Previously, Dane Chetkovich, MD, PhD, and colleagues investigated how antidepressant drugs work, including why they require weeks to begin taking effect.
They also uncovered a new drug target in major depressive disorder, TRIP8b, an auxiliary subunit of the HCN channel, which is an ion transporter channel, or pore, in nerve cell membranes. In a mouse model of depression, disrupting the TRIP8b-HCN interaction had antidepressant effects, rescuing cognitive function and motivated behavior.
In new experiments reported in the Journal of Biological Chemistry, Chetkovich, Ye Han, PhD, and colleagues used in silico methods to screen millions of compounds, looking for a small molecule that might disrupt the TRIP8b-HCN interaction.
This led to selective lab testing, in which a compound known as NUCC-0200590 showed special promise. Extensive in vitro analyses provided details on how this now confirmed inhibitor disrupts the TRIP8b-HCN interaction. Testing in mice confirmed the compound’s promise as a new, mechanistically distinct and rapid-acting therapy for major depressive disorder.
Others on the study from VUMC include Chengwen Zhou, PhD, Ioannis Michailidis, PhD, and Maya Xia. They were joined by investigators from Northwestern University and Stanford University. The study was supported by the National Institutes of Health (MH106511).