ABSTRACT

The objective of pharmaceutical research is to discover and develop new substances that can be characterized by their selectivity and specicity. Selectivity describes the particular effects on physiological or pathological states that the substance can produce. These descriptions, such as hypnotic, hypoglycemic, hypotensive, and antiinammatory, may be wholly empirical; however, this does not impede their therapeutic utility. Thus, the clinical utility of drugs such as morphine and digitalis was established long before we had biochemical explanations for their actions. Specificity, on the other hand, refers to the biochemical hypotheses that claim to explain the selectivity of a substance. Thus, activation of enkephalin receptors is proposed as the mechanism by which morphine acts, and inhibition of Na+-/K+-dependent adenosine triphosphatase (ATPase) has been claimed to specify the activity of digitalis. All kinds of biochemical events have been used to specify drug actions. Interactions with enzymes, ion channels, and membrane transporters have been widely used to explain drug actions. However,

9.1 Hormone Receptors ..............................................................................................................269 9.2 Partial Agonists: Problems in Detecting Changes in Efcacy ............................................. 270 9.3 The Value of Bioassays ......................................................................................................... 271 9.4 Are Bioassays Valuable in Pharmaceutical Research? ......................................................... 272 9.5 The Iterative Process of Drug Development ......................................................................... 273 9.6 Me-Tooism ............................................................................................................................ 274 9.7 Short-Termism ...................................................................................................................... 274 9.8 Combinatorial Chemistry ..................................................................................................... 275 9.9 Selecting Targets for Drug Development.............................................................................. 276

pharmacological receptors are probably the favorite site of drug action used in explanatory models of their selective activity.