Drug Therapy Aimed at Adenylyl Cyclase to Regulate Cyclic Nucleotide Signaling

Conventional drug screening has been targeted, in many cases, on cell surface receptors, e.g., G-Protein coupled receptors, to regulate cellular signaling and thus function. There is emerging evidence, however, that such targets can be expanded to effector enzymes of receptors because effector enzymes have multiple subtypes that differ in tissue distribution, and thus targeting such molecules may lead to organ-specific pharmacological regulation. An example is phosphodiesterase, which degrades cyclic nucleotides. Subtype-specific phosphodiesterase inhibitors, such as sildenafil citrate, a type 5 phosphodiesterase inhibitor, and milrinone, a type 3 phosphodiesterase inhibitor, are now widely used in the treatment of erectile dysfunction and heart failure, respectively. Adenylyl cyclase, which synthesizes cyclic AMP, has at least 9 isoforms that differ in tissue distribution. Transgenic mouse studies utilizing such isoforms have identified the roles of each isoform. Forskolin, a natural plant extract, was first identified as a general stimulator of adenylyl cyclase more than 20 years ago. Recently, 6-[3-(dimethylamino)propionyl]forskolin, a water-soluble forskolin derivative with high selectivity for type 5 (cardiac) adenylyl cyclase was developed and has been widely used in the treatment of acute heart failure. Adenine analogs or P-site inhibitors, which are classic, but not isoform-specific adenylyl cyclase inhibitors, are now utilized to develop isoform-specific inhibitors as well. Putting together, targeting adenylyl cyclase isoforms, either of isoform-specific stimulation or inhibition, may be a novel strategy to develop new drugs in the next decade.