Determination of the functional dissociation constant of a partial agonist by comparison with a higher efficacy agonist

Abstract

A formula derived by Gero and Tallarida (1977) relates the equilibrium dissociation constant of a partial agonist (P) and that of a second agonist (A) of greater efficacy that acts on the same receptor. The second agonist may or may not be a strong agonist. Accordingly, if the dissociation constant (K) of one of the compounds is known, say from the method of partial irreversible receptor blockade, then the dissociation constant for the other may be determined from the complete concentration-effect curves of the compounds and the derived formula: $\text{K}{}_{\mathrm{p}}\text{=}\text{K}{}_{\mathrm{A}}\text{(A}{}_{\mathrm{p}}\text{− A}{}_{\mathrm{i}}\text{)}\text{P}{}_{\mathrm{i}}\text{/(A}{}_{\mathrm{p}}\text{+ K}{}_{\mathrm{A}}\text{)A}{}_{\mathrm{i}}\text{,}\text{where}\text{P}{}_{\mathrm{i}}\text{and}\text{A}{}_{\mathrm{i}}$ are equieffective concentrations of P and A, A_p = the concentration of A that gives an effect = the maximum effect of P. The practical use of this formula is illustrated here for several agonists, and for each, the value of K obtained is compared to that obtained by partial irreversible receptor blockade. In all cases tested, the agreement is quite good, thus suggesting that this method may be a practical alternative.