Highly Functionalized Terpyridines as Competitive Inhibitors of AKAP–PKA Interactions**

Protein kinase A (PKA) is a ubiquitous kinase that phosphorylates a broad variety of substrates. A-kinase anchoring proteins (AKAPs) confer specificity to PKA signaling by tethering the kinase to distinct cellular compartments, thereby limiting the access of PKA to a defined pool of its substrates. Interactions between AKAPs and PKA play key roles in a plethora of physiologically relevant processes such as arginine-vasopressin (AVP) mediated water reabsorption in renal principal cells; AVP triggers PKA phosphorylation of the water channel aquaporin-2 (AQP2). AQP2 then redistributes from intracellular vesicles into the plasmamembrane, thereby facilitating water reabsorption from primary urine. The redistribution only occurs if PKA interacts with AKAPs. Dysregulation of cellular processes that depend on AKAP–PKA interactions causes or is associated with diseases. For example, in heart failure, elevated AVP levels contribute to the excessive water retention by the above-described mechanism. Cardiac myocyte contractility is decreased in the failing heart; the control of contractility crucially depends on AKAP–PKA interactions. PKA holoenzyme is a tetramer consisting of a dimer of regulatory (RIa, RIb, RIIa, or RIIb) and two catalytic (C) subunits each bound to an R protomer. Upon binding of cAMP to the R subunits, the C subunits dissociate and phosphorylate their substrates. Interactions of PKA with AKAPs are mediated by the dimerization/docking (D/D) domains of R subunit dimers and the RII binding domain (RBD) of AKAPs. Dimerized D/D domains form a hydrophobic pocket that directly interacts with the 14–25 amino acid long a-helical RBD. Synthetic peptides derived from RBDs of different AKAPs bind R subunits with nanomolar affinity, for example, AKAP18d-L314E from AKAP18d (KD= 4 nm ; see Figures S1 and S2 as well as Table S2 in the Supporting Information). Such peptides effectively inhibit AKAP–PKA interactions. For example, membrane-permeable versions of AKAP18d-L314E and Ht31 (from AKAP-Lbc) abolish the AVP-induced redistribution of AQP2 in cultured principal cells. Thus disruption of AKAP–PKA interactions even appears beneficial for the treatment of diseases, such as heart failure, that are associated with AVP-dependent excessive water retention. As a consequence of their generally low membrane permeability and stability, peptides have limitations with regard to their use in cell and animal studies and for drug development. Small molecules and nonpeptide helix mimetics are considered as alternatives to peptides, and thus the small molecule FMP-API-1 was developed that inhibits AKAP– PKA interactions. However, FMP-API-1 also activates PKA,