Enthalpy-entropy relationship in drug-cholinoceptor interaction: a new approach.

The partial molal volume at infinite dilution, V2, was determined in toluene, benzene and acetonitrile for fifteen different drug molecules comprising muscarinic agonists, partial agonists and antagonists. The difference in V2 between a given drug, X, and hyoscine, expressed as (V2x - V2h) was then multiplied by the internal pressure of the holding phase (Pi approximately cohesive energy density) in order to obtain an estimate of the excess enthalpy (delta H) over hyoscine in the interaction of drug molecule X with a common cholinoceptor. As a working hypothesis, delta H for hyoscine is taken as zero, hyoscine having the lowest V2/affinity ratio of any drug in the series investigated. The corresponding change in entropy (delta S) was then calculated from the relationship: RT ln Kx = Pi(V2x - V2h) - T delta S, where Kx is the affinity constant of drug molecule X to the common cholinoceptor, obtained independently. Linear regression of Pi (V2x - V2h) congruent to delta H from the data in acetonitrile over delta S gave a satisfactory isoequilibrium plot, r2 = 0.954, slope (beta) = 231 degrees K. The present approach offers a new course for the study of the enthalpy-entropy relationship in the interaction of drug molecules in a given series with a common receptor. It could provide an alternative to the Van't Hoff procedure for the estimation of relative delta H, and is independent of the free energy of binding (delta G).