No meth heads on the staff? –
Sep. 21, 2020 – Thus began a quest to find a molecule that would maintain lobeline’s ability to inhibit the target VMAT2, but would be safe and effective for human use. Also, the researchers sought a compound that could be taken orally. Over the years, however, the team’s path was littered with frustrating results for their potential candidate molecules. One molecule showed poor bioavailability; another one was chemically unstable. Still others showed only weak interactions with VMAT2 or caused adverse effects such as cardiotoxicity or liver toxicity. There was particular disappointment with a molecule named GZ-793A, which seemed to check all the boxes but was then shown to change ion flow through a cardiac protein pore called the hERG channel, potentially sparking cardiac arrythmia.
Nevertheless, these early tests yielded valuable information—for example, ruling out unwanted effects. “At first, it was confusing for staff and students because nothing was happening in some of the off-target assays that they were performing,” Dr. Dwoskin reminisces. “But sometimes finding nothing is a good thing. It means a compound has good selectivity for the target and theoretically has no side effects. Over time, you learn that drug discovery is a high-risk, high-gain sort of effort.”