Cyclic nucleotide analogs as biochemical tools and prospective drugs

Cyclic AMP (cAMP) and cyclic GMP (cGMP) are key second messengers involved in a multitude of cellular events. From the wealth of synthetic analogs of cAMP and cGMP, only a few have been explored with regard to their therapeut ic potential. Some of the first-generation cyclic nucleotide analogs were p romising enough to be tested as drugs, for instance N-6,O-2'-dibutyryl-cAMP and 8-chloro-cAMP (currently in clinical Phase II trials as an anticancer agent). Moreover, 8-bromo and dibutyryl analogs of cAMP and cGMP have becom e standard tools for investigations of biochemical and physiological signal transduction pathways. The discovery of the Rp-diastereomers of adenosine 3',5'-cyclic monophosphorothioate and guanosine 3',5'-cyclic monophosphorot hioate as competitive inhibitors of cAMP- and cGMP-dependent protein kinase s, as well as subsequent development of related analogs, has proven very us eful for studying the molecular basis of signal transduction. These analogs exhibit a higher membrane permeability, increased resistance against degra dation, and improved target specificity. Furthermore, better understanding of signaling pathways and ligand/protein interactions has led to new therap eutic strategies. For instance, Rp-8-bromo-adenosine 3',5'-cyclic monophosp horothioate is employed against diseases of the immune system. This review will focus mainly on recent developments in cyclic nucleotide-related bioch emical and pharmacological research, but also highlights some historical fi ndings in the field. (C) 2000 Elsevier Science Inc. All rights reserved.