ACT-132577 is an active metabolite of Macitentan that acts as an endothelin B (ET-B) and endothelin A (ET-A) receptor antagonist. ACT-132577 antagonizes the specific binding of endothelin-1 on membranes of cells overexpressing ET-A and ET-B receptors with IC₅₀ values of 3.4 nM and 987 nM, respectively¹. It also has the ability to reach full inhibition of intracellular Ca²⁺ increase induced by endothelin-1 on non-recombinant cells¹.

Endothelin receptors belong to the superfamily of G-protein coupled receptors and include two subtypes: ET-A and ET-B. ET-A receptors are predominantly expressed in peripheral tissues, especially in vascular smooth muscle tissues to mediate vasoconstriction. They are also present in several different regions of the brain. ET-B receptors play an important role in regulating renal function and blood pressure and are expressed in sensory nerves. They are mainly detected in medium- and large-sized cell bodies of human trigeminal ganglia.

The ET-A receptor has high affinity for endothelin-1 and endothelin-2 and relatively low affinity for endothelin-3, while the ET-B receptor has high affinity for all endothelin isopeptides^2,3_.