A water-soluble receptor for adenosine derivatives was synthesized for the study of molecular recognition in aqueous solution. The modular receptor makes use of hydrophobic interactions, Watson-Crick and Hoogsteen hydrogen-bonding, and a phosphate-guanidinium electrostatic interaction to bind cyclic adenosine monophosphates. Measured binding affinities of 2’,3/-cAMP are -3.65 and -3.26 kcal/mol at 51 and 501 mM ionic strength, respectively (H2O/D2O solution at 10 degrees C, pH 6.0). The phosphate-guanidinium interaction in this system is estimated to contribute on average 0.6 kcal/mol (51 mM ionic strength) and 0.3 kcal/mol (501 mM ionic strength) to binding. The maximum value of a phosphate-guanidinium electrostatic interaction is estimated to be 2.4 kcal/mol in water.