Abstract
Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular matrix synthesis. Selexipag (Uptravi®) is the first non-prostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy, ACT-333679 (previously known as MRE-269), behaved as full agonist in multiple PAH-relevant receptor-distal - or downstream - cellular readouts with a maximal efficacy comparable to that of the prototypic PGI2 analog iloprost: In PASMC, ACT-333679 potently induced cellular relaxation (EC50=4.3 nM), inhibited cell proliferation (IC50=4.0 nM) as well as extracellular matrix synthesis (IC50=8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal - or upstream - cAMP accumulation assays (Emax=56%) when compared to iloprost (Emax=100%) and the PGI2 analogs beraprost and treprostinil. Partial agonism of ACT-333679 also resulted in limited β-arrestin recruitment (Emax=40%) and lack of sustained IP receptor internalization, whereas all tested PGI2 analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.
- biased agonism
- cardiovascular drugs
- G protein coupled signaling
- pulmonary hypertension
- receptor desensitization
- The American Society for Pharmacology and Experimental Therapeutics