Receptor theories and quantitative effect versus dose-concentration relationship

Both in vivo and in vitro, the dissociation constant K not equal to D50. This was shown for morphine in vivo and for several vasoconstrictors in isolated vascular smooth muscle. When Schild plots are made for a pure competitive antagonist the underlying theory requires that the regression line be constrained to slope -1, for only in this case does pA2 = -log KB, and each has the same confidence limits. Further, even where the slope of the conventional (unconstrained) regression line differs only slightly from -1, the confidence limits of pA2 differ appreciably from those of -log KB. Values of K obtained from pharmacologic methods can discriminate among receptor subtypes. A proper determination of K permits knowledge of the stimulus-response relation, a drug-independent property of the effector system. A perturbation of the drug-receptor equilibrium is a way of determining both k1 and k2; so far, however, we have been successful only with alpha-adrenergic vasoconstrictors in which UV light is a suitable stimulus. Radiolabeled binding appears to be a precise way of determining K's for agonists and antagonists. However, it does not measure an effect; hence we do not know that such binding sites are true receptors unless we can find a correlation between the values obtained for a series of drugs with this method and those obtained with appropriate pharmacologic methods.