Cyclic nucleotide analogs as biochemical tools and prospective drugs

• Published in: Pharmacology & therapeutics (Oxford) Vol. 87; no. 2; pp. 199 - 226
• Main Authors: Schwede, Frank, Maronde, Erik, Genieser, Hans-Gottfried, Jastorff, Bernd
• Format: Book Review Journal Article
• Language: English
• Published: England Elsevier Inc 01-08-2000
• Subjects: 8-Chloro cyclic AMP; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Asthma - drug therapy; cAMP-dependent protein kinase; cGMP-dependent protein kinase; Clinical studies; Clinical Trials as Topic; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic AMP-Dependent Protein Kinases - pharmacokinetics; Cyclic AMP-Dependent Protein Kinases - therapeutic use; Cyclic GMP - physiology; Cyclic GMP-Dependent Protein Kinases - metabolism; Cyclic GMP-Dependent Protein Kinases - pharmacokinetics; Cyclic GMP-Dependent Protein Kinases - therapeutic use; Cyclic nucleotide analogs; Humans; Hypertension - drug therapy; Neoplasms - drug therapy; Receptors, Cyclic AMP - physiology; Signal Transduction; 8-Br-cGMP, 8-bromo-cyclic GMP; CREB, cyclic AMP responsive element binding; PET-cGMP, β-phenyl-1, N 2-etheno-cyclic GMP; PKG, protein kinase G; Cyclic nucleotide analogs; 8-pCPT-cAMP, 8- para-chlorophenylthio-cyclic AMP; PDE, phosphodiesterase; Rp-8-Br-cAMPS, Rp-8-bromo-adenosine 3′,5′-cyclic monophosphorothioate; 8-Chloro cyclic AMP; Bt 2-cAMP, N 6, O 2′-dibutyryl-cyclic AMP; C, catalytic; Sp-cGMPS, Sp-diastereomer of guanosine 3′,5′-cyclic monophosphorothioate; cAMP, cyclic AMP; 8-pCPT-cGMP, 8- para-chlorophenylthio-cyclic GMP; Clinical studies; PKA-II, protein kinase A Type II; CNG, cyclic nucleotide-gated; cNMP, cyclic nucleotide monophosphate; N 2-Bt-cGMP, N 2-monobutyryl-cyclic GMP; Sp-cAMPS, Sp-diastereomer of adenosine 3′,5′-cyclic monophosphorothioate; ICER, inducible cyclic AMP early repressor; Rp-cGMPS, Rp-diastereomer of guanosine 3′,5′-cyclic monophosphorothioate; HIV, human immunodeficiency virus; 8-Br-cAMP, 8-bromo-cyclic AMP; Bt 2-cAMP/AM, Bt 2-cAMP acetoxymethyl ester; R, regulatory; cAMP-dependent protein kinase; 6-MBC-cAMP, N 6-mono- tert-butylcarbamoyl-cyclic AMP; Epac, exchange protein directly activated by cyclic AMP; cGMP, cyclic GMP; Rp-8-Br-PET-cGMPS, Rp-8-bromo-β-phenyl-1, N 2-etheno-guanosine 3′,5′-cyclic monophosphorothioate; Rp-cAMPS, Rp-diastereomer of adenosine 3′,5′-cyclic monophosphorothioate; NK, natural killer; IL, interleukin; Bt 2-cGMP, N 2, O 2′-dibutyryl-cyclic GMP; CVI, common variable immunodeficiency; ST a, heat-stable enterotoxin from Escherichia coli; PKA, protein kinase A; MDR, multidrug resistance; cGMP-dependent protein kinase; Sp-5,6-Cl 2-cBIMPS, Sp-5,6-dichloro-1-β- d-ribofuranosyl-benzimidazole-3′,5′- cyclic monophosphorothioate; TCR, T-cell receptor; Sp-8-Br-PET-cGMPS, Sp-8-bromo-β-phenyl-1, N 2-etheno-guanosine 3′,5′-cyclic monophosphorothioate; PVR, pulmonary vascular resistance; NO, nitric oxide; AC, adenylate cyclase; GLP, glucagon-like peptide; PKA-I, protein kinase A Type I; AM, acetoxymethyl; 8-Cl-cAMP, 8-chloro-cAMP; GC, guanylate cyclase; GEF, guanine nucleotide exchange factor; HCN, hyperpolarization-activated, cyclic nucleotide-gated; N 6-Bt-cAMP, N 6-monobutyryl-cyclic AMP
• ISSN: 0163-7258; 1879-016X
• DOI: 10.1016/S0163-7258(00)00051-6

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 therapeutic potential. Some of the first-generation cyclic nucleotide analogs were promising 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 become 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 monophosphorothioate as competitive inhibitors of cAMP- and cGMP-dependent protein kinases, as well as subsequent development of related analogs, has proven very useful for studying the molecular basis of signal transduction. These analogs exhibit a higher membrane permeability, increased resistance against degradation, and improved target specificity. Furthermore, better understanding of signaling pathways and ligand/protein interactions has led to new therapeutic strategies. For instance, Rp-8-bromo-adenosine 3′,5′-cyclic monophosphorothioate is employed against diseases of the immune system. This review will focus mainly on recent developments in cyclic nucleotide-related biochemical and pharmacological research, but also highlights some historical findings in the field.