PE-22-28 has a disjointed history behind its discovery that appears confusing at first, so I’ll first need to talk about two of its predecessor molecules.

Back in 2006, the TWIK-related potassium channel-1 (TREK-1) protein was discovered as a potential drug target for treating depression:

“The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT [serotinin].

In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress.

TREK-1-deficient (Kcnk2-/-) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine”

From this emerged a new goal for scientists: Inhibit TREK-1 via a potent antagonist and you have a shot at fixing depression.