Several 8-substituted derivatives of guanosine 3 ',5'-cyclic phosphate (cGMP), inosine 3'.5 '-cyclic phosphate (cIMP), and xanthosine 3 ',5 '-cyclic phosphate (cXMP) were synthesized and their biochemical properties compared to corresponding 8-substituted adenosine 3 ',5 '-cyclic phosphate (CAMP) derivatives. cGMP was brominated to give 8bromo-cGMP which was subsequently used to synthesize ciri nucleophilic reactions, %hydroxy-, 8-dimethylamino-, 8methylamino-, 8-benzylamino-, 8-p-chlorophenylthio-, 8benzylthio-, and 8-methylthio-cGMP. Deamination of cGMP and 8-bromo-cGMP gave cXMP and 8-bromo-cXMPj respectively. were prepared by deamination of the respective 8-substituted CAMP. Hydrogenation of 8-azido-cIMP gave 8-amino-cIMP. Thiation of 8-bromo-cIMP gave 8-thio-cIMP.The substituted cGMP derivatives were specific for lobster rnuscle cGMP-dependent protein kinase whereas the 8-substituted cAMP derivatives were specific for bovine brain

Various derivatives of adenosine 3',5'-cyclic phosphate, most notably vV^'-O-dibutyryl-cAMP1 and several 8-alkylthio-cAMP analogs (Free et al., 1972), have been shown to be more effective than cAMP itself in many whole cell systems (see reviews by Robison et Severson, 1971). Reasons for the low activity of cAMP might include the low permeability of cAMP across cell membranes and its intracellular or extracellular hydrolysis by cAMP phosphodiesterase. It has been proposed that 7V6,2'-0-dibutyryl-cAMP is both more rapidly transported across cell membranes and less rapidly hydrolyzed by the phosphodiesterase (Posternak et al., 1962; Robison et al., 1971). It has further been suggested that the acylated derivatives of cAMP

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We report on a new synthesis of several novel 6substituted derivatives of 9-,8-D-ribofuranosylpurine 3',5'cyclic phosphate. These analogs were shown to be more readily cleaved by rabbit kidney and pig brain phosphodiesterase than the corresponding 8-substituted compounds (viz., 8-SH, SCH3, SC2Hs, SCH2C6H5) previously reported upon. In addition, several of the 6-alkylthio derivatives were up to two times more active than cAMP as alternate activators