The melatonin receptor is a G protein-coupled receptor (GPCR) that binds to melatonin. Specifically, receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin is the key factor of clock synchronization. Besides, Melatonin receptors are found in all parts of the body, such as the brain, retina of the eye, cardiovascular system, liver, etc. Moreover, Melatonin has many functions in the whole body. In addition to promoting sleep, melatonin also regulates hormone secretion, reproductive rhythm, immune function, and circadian rhythm. In addition, melatonin has neuroprotective, pain-relieving, tumor-inhibiting, reproductive, and antioxidant effects. Furthermore, Melatonin has an anti-excitatory effect on brain activity.

Genetic mutation of melatonin receptor is relevant to melatonin signal transduction. Meanwhile, it results in increased fasting blood glucose level, impaired islet secretion, and increased risk of type 2 diabetes. Nonetheless, Melatonin administration can improve liver steatosis, inflammatory markers, and lipid levels in high-fat diet-induced obese (DIO) mice. The physiological effects of melatonin occur through different molecular pathways, involving the activation of GPCR called MT1 and MT2. Today, we will introduce an orally active melatonin receptor agonist, ACH-000143.

ACH-000143 is an Orally Active Melatonin Receptor Agonist.

At first, ACH-000143 is a potent and orally active melatonin receptor agonist. Importantly, ACH-000143 has EC50 values of 0.06 nM and 0.32 nM for MT1 and MT2, respectively. Interestingly, ACH-000143 has a stronger regulatory effect on peripheral absorption and liver lipid metabolism than central exposure

Taken together, ACH-000143 with 10-30 mg/kg/day orally for two months significantly reduced the weekly BW gain on weeks. Particularly, ACH-000143 reduces liver triglycerides and steatosis in diet-Induced obese rats. Obviously, ACH-000143 is devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o.. ACH-000143 significantly reduces plasma glucose at 10 mg/kg (−16.4%) and 30 mg/kg (−16.9%). By the way, ACH-000143 results in improved glucose plasma and HOMA-IR. It significantly reduced weight gain, and improved glycemic control, insulin sensitivity, and hepatic triglyceride concentration.

All in all, ACH-000143 is a potent and orally active melatonin receptor agonist.


Marcos Antonio Ferreira Jr, et al. J Med Chem. 2021 Feb 25;64(4):1904-1929.