G-protein coupled receptor kinases and their inhibitors

AbstractG-protein coupled receptors (GPCRs) are regulated by several processes. One is the phosphorylation by G-protein coupled receptor kinases (GRKs) linked to processes like receptor desensitisation, internalisation and downregulation. GRKs also seem to be involved in various processes such as opioid addiction and cardiovascular diseases. So far, no specific and potent inhibitors of GRKs are available except some polyanionic compounds like heparin. A rational approach for a search for inhibitors based on a homologous molecular model of GRK2 revealed disulphonic acid analogues of suramin (NF503 and NF062) as lead compounds for inhibitors of GRK2 (IC50 values of 14 and 25 μM, respectively). GRK2 is extensively expressed in the CNS and therefore, mainly considered responsible for the regulation of GPCRs. So far, no therapeutic patents for inhibition of GRKs are available. Nevertheless, a broad range of serine/threonine kinase inhibitors are reported in the patent literature. An overview of these mainly N-heterocyclic or amino group containing compounds is given in this review. Furthermore, other approaches to inhibit GRKs such as the use of antibodies, antisense oligonucleotides, or adenoviral mediated gene delivery of a peptide inhibitor of GRK2 are presented. Screening against various GRKs is likely to yield new lead compounds to further evaluate a (patho)physiological role of GRKs. Possible therapeutic applications of GRK inhibitors are discussed.KeywordsdesensitisationG-protein coupled receptor kinaseG-protein coupled receptor regulationheart failurehypertensionNF503opiate addictionserine/threonine kinasesuramin