Heart failure is a serious and common disease, and as of today there is no cure available and medical treatment serves only to postpone further development and improve life quality. Treatment of mild to moderate heart failure usually consists of a regimen of drugs, often including β-blockers. Despite the advance in therapeutics, morbidity and mortality of heart failure is high and it remains to find suitable new therapeutic targets.The β-adrenergic receptor-cAMP-protein kinase A (PKA) signaling pathway regulates heart rate and contractility. Phospholamban (PLB) is a key regulator of cardiac contraction and modulates sarcoplasmic reticulum (SR) Ca2+ re-uptake by binding to and thereby inhibiting the SR Ca2+-ATPase (SERCA2) in its dephosphorylated state. Upon phosphorylation by PKA the inhibitory effect of PLB on the function of SERCA2 is released. There has been identified an A-kinase anchoring protein (AKAP), AKAP18δ, in SR that is in complex with PLB and recruits PKA to its substrate. This supramolecular complex controls the adrenergic effect on Ca2+ re-uptake and the heart relaxation which is rate-limiting for increasing the heart rate. Inhibition of AKAP18δ-PLB interactions may provide a specific reduction in β-adrenergic stimulation and could isolate one effect of β-blockers possibly making therapy more targeted and avoid side effects. This blocking effect is believed to protect from reperfusion damage in the post-infarction heart and to have effect in chronic heart failure.Screening for small molecular compounds disrupting the AKAP18δ-PLB interaction was done using the AlphaScreen technology. A sub-library screen of 80 compounds served to delineate this group and define its structural properties in disrupting the AKAP18δ-PLB interaction. Next three series of altogether 23 compounds were newly synthesized and characterized leading to identification of non-toxic compounds with 100-fold improved efficacy and definition of a pharmacophoric group for disruptors of the AKAP18δ-PLB interaction which modifies PLB phosphorylation.