Inhibitors of membranous adenylyl cyclases

Membranous adenylyl cyclases (mACs) constitute a family of nine isoforms with different expression patterns. Studies with mAC gene knockout mice provide evidence for the notion that AC isoforms play distinct (patho)physiological roles. Consequently, there is substantial interest in the development of isoform-selective mAC inhibitors. Here, we review the current literature on mAC inhibitors. Structurally diverse inhibitors targeting the catalytic site and allosteric sites (e.g. the diterpene site) have been identified. The catalytic site of mACs accommodates both purine and pyrimidine nucleotides, with a hydrophobic pocket constituting a major affinity-conferring domain for substituents at the 2′- and 3′-O-ribosyl position of nucleotides. BODIPY-forskolin stimulates ACs 1 and 5 but inhibits AC2. However, so far, no inhibitor has been examined at all mAC isoforms, and data obtained with mAC inhibitors in intact cells have not always been interpreted cautiously enough. Future strategies for the development of the mAC inhibitor field are discussed critically.