Second messenger systems as targets for new therapeutic agents: focus on selective phosphodiesterase inhibitors

Second messengers are intracellular substances whose concentration is regulated by the action on their specific receptors of extracellular regulatory molecules globally known as first messengers. In particular, the cyclic nucleotides cAMP and cGMP help in the coordination of cellular functions, mainly through their stimulatory effect on multisubstrate protein kinases. The pharmacological modulation of cyclic nucleotide levels has been classically attained by acting on the first messenger receptors. However, the possibility exists that an intervention on the enzymes responsible for the synthesis or degradation of such second messengers could yield similar effects. The enzymes involved in the degradation of cAMP and cGMP, the so-called cyclic nucleotide phosphodiesterases (PDEs), are a group of at least 7 enzyme families that share the property of hydrolysing the cyclic nucleotides to their corresponding 5-monophosphate counterparts. At the present time, most of the interest on the potential utility of selective PDE inhibitors is focused on drugs capable of inhibiting PDE IV, one of the cAMP specific phosphodiesterases, because the tissue distribution of PDE IV strongly suggests that pathologies related to the central nervous and immune systems, could be treated in this way. PDE IV inhibitors can be divided into three structural classes: 1) structural analogues of rolipram, 2) structural analogues of nitraquazone and 3) structures related to the xanthine nucleus, such as denbufylline. An overview of the structure-activity relationships for these classes of compounds and a summary of their possible therapeutic potential will be given.