AKU-005

AKU-005 is a **small molecule inhibitor** that acts as a potent triple inhibitor of the endocannabinoid hydrolases monoacylglycerol lipase (**MAGL**), fatty acid amide hydrolase (**FAAH**), and alpha/beta-hydrolase domain-containing protein 6 (**ABHD6**)[1][4][14]. By inhibiting these enzymes, AKU-005 increases levels of endocannabinoids such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), which play a role in pain modulation and neuroinflammation. It has demonstrated efficacy in preclinical models by reducing cortical spreading depression (CSD), a phenomenon linked to **migraine with aura**, and by reducing NTG-induced hyperalgesia and inflammation in rat models[1][2][14]. AKU-005 demonstrates species differences in efficacy: it potently inhibits MAGL, FAAH, and ABHD6 in rats, but primarily MAGL in mice[1][4]. Its anti-migraine effect appears mediated both by endocannabinoid tone enhancement and anti-inflammatory actions, including suppression of CGRP release and pro-inflammatory cytokines in relevant central and peripheral nervous system regions[2].