ESTIMATION OF PARTIAL AGONIST AFFINITY BY INTERACTION WITH A FULL AGONIST - A DIRECT OPERATIONAL MODEL-FITTING APPROACH

1 The operational model of agonism (Black & Leff, 1983) has been exten ded to describe the interaction between a partial agonist and a full a gonist at the same receptor. The derived equation explicitly describes the interaction and allows the affinity (and efficacy) of the partial agonist to be estimated by direct fitting of raw experimental agonist concentration-effect (E/[A]) curve data. 2 The model was used to anal yse experimental E/[A] curve data generated for the interaction betwee n pilocarpine (partial agonist) and carbachol (full agonist) at the M3 -muscarinic receptor mediating contraction of the guinea-pig isolated trachea. Pilocarpine affinity estimates obtained by operational model- fitting were compared with those obtained by use of the null method (S tephenson, 1956). These analyses demonstrated that the two methods gav e comparable results (mean pK(B) estimates were 5.79 and 5.86 for the operational model and null method respectively). 3 When multiple conce ntrations of partial agonist are used, simultaneous operational model- fitting of all the E/[A] curve data allows the competitive nature of t he interaction to be studied. 4 We conclude that operational model-fit ting is a valid and analytically simple alternative to the conventiona l null method of analysing full/partial agonist interactions.