Talk by: Dr. Ronald J. Tallarida, Ph.D., Temple University Medical School, Dept. of Pharmacology

Title: Theory of Drug Action

Abstract: The theory of drug action is based on a model in which the drug molecule interacts with a site, called a receptor, located on (or in) the cell. The interaction is modeled as a bimolecular reversible reaction that follows from the law of mass action. The effect (E) produced by the drug is taken to be a function of the number of occupied receptors (X) and a specific constant, epsilon , known as intrinsic activity; thus E = f( epsilon X). Therefore, in order to be effective, (1) the drug must have affinity for the receptor and (2) the occupied receptor must have the ability to produce a sufficient signal that produces the effect. Information related to drug-receptor affinity comes from laboratory procedures that radiolabel the drug molecule and determine its specific binding to cell membrane fractions. Information on the magnitude of the effect, and its relation to the dose of the drug, comes from experiments in animal species or tissues derived from the animals that received the drug. The theory couples the dose-effect data to the intimate events surrounding the drug’s binding to the receptor. Classical drug-receptor theory is based on an old model in which the drug molecule combines with a single receptor type. Much recent evidence (using radioligand binding) has shown that most drugs interact with more than one receptor type—each having its own affinity and dissociation rate constants. The theory must therefore be revised in order to account for the multiple receptor types and the contribution that each makes to the effect. To accomplish this, advanced modeling is underway by our group, but this activity requires data describing receptor binding and dose-effect relations. The data base is extensive, even for a single drug group such as the opioids. Moreover, it is widely scattered and not well organized. Even for a single drug in the opioid group its binding at different anatomical sites will vary and its binding affinity to different receptors at these sites will also vary. When the drug is used in an animal experiment different routes of administration are used, and various effects are measured. Thus, data from laboratory procedures (binding to different receptors and sites), route of administration (pharmacokinetics), and dose-effect relations must be gathered and incorporated in our various models. We aim to develop and test a broadened theory as applied to drugs of the opioid class. These are known to have at least three distinct receptors (termed mu, delta, kappa). Affinity constants for each receptor type (and drug) are needed. Also, these drugs typically produce effects of various kinds, e.g., analgesia (as measured by several tests), gastrointestinal inhibition, respiratory depression, and body temperature changes. The huge amount of information must be efficiently collected, organized and incorporated in a revised theory that recognizes the reality of multiple receptors and quantitates their contribution. There is a strong need to utilize specialists in data mining who can develop the methods and algorithms for retrieving and analyzing subsets of opioid data that appear in numerous publications throughout the world.