Urocortin-2

UCN2 binds CRFR2 with high affinity and negligible affinity for CRFR1. CRFR2 is expressed in cardiac muscle, smooth muscle, and skeletal muscle. In the heart, CRFR2 activation increases cAMP through Gs coupling, activating PKA and enhancing cardiac contractility (positive inotropy). In vascular smooth muscle, CRFR2 activation causes relaxation, reducing systemic vascular resistance.

UCN2 reduces ischemia-reperfusion injury through CRFR2-dependent activation of cardioprotective kinases (PI3K/Akt, ERK) and inhibition of mitochondrial permeability transition pore opening. It also reduces cardiomyocyte apoptosis and promotes cardiac regenerative signaling. Chronic UCN2 infusion in heart failure models improves remodeling outcomes.

Phase 2 trials in patients with systolic heart failure demonstrated that a 5-hour IV infusion of UCN2 significantly improved cardiac output, reduced pulmonary capillary wedge pressure, and decreased systemic vascular resistance versus placebo. Hemodynamic benefits persisted for several hours post-infusion. UCN2 is being evaluated as an acute decompensated heart failure therapy.

UCN2 infusion reduces food intake and body weight in rodent models through CRFR2 activation in the hypothalamus and periphery. It also improves insulin sensitivity and skeletal muscle glucose uptake. These metabolic effects suggest potential applications in obesity and type 2 diabetes, though CRFR2 is not the primary target of current metabolic drugs.