Drug-receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of receptor-recognition phenomena. The large number of membrane receptors so far studied has led to the discovery of enthalpy-entropy compensation effects in drug-receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 degrees C appears enthalpy/entropy-driven (-53.0 </= DeltaG degrees </= -48.6, -34.5 </= DeltaH degrees </= -19.9 kJ/mol, 0.057 </= DeltaS degrees </= 0.111, and -2.4 </= DeltaC(p) degrees </= -1.7 kJ mol(-1) K(-1)) and is interpreted in terms of hydrophobic and hydrogen-bonded specific interactions. Results obtained for cytoplasmic receptors are extensively compared with those known for typical membrane receptors, in particular the adenosine A(1) receptor, to investigate the thermodynamic bases of drug-receptor binding from the most general point of view.